U.S. patent number 7,786,116 [Application Number 12/362,020] was granted by the patent office on 2010-08-31 for 2-amino-quinoline derivatives useful as inhibitors of .beta.-secretase (bace).
This patent grant is currently assigned to Janssen Pharmaceutica N.V.. Invention is credited to Ellen Baxter, Christopher J. Creighton, Chih Yung Ho, Yifang Huang, Tianbao Lu, Chi Luo, Allen B. Reitz, Charles H. Reynolds, Tina Morgan Ross, Ellen Sieber-McMaster.
United States Patent |
7,786,116 |
Baxter , et al. |
August 31, 2010 |
2-amino-quinoline derivatives useful as inhibitors of
.beta.-secretase (BACE)
Abstract
The present invention is directed to novel 2-amino-quinoline
derivatives, pharmaceutical compositions containing them and their
use in the treatment of Alzheimer's disease (AD), mild cognitive
impairment, senility and/or dementia. The compounds of the present
invention are inhibitors of .beta.-secretase, also known as
.beta.-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or
memapsin2.
Inventors: |
Baxter; Ellen (Glenside,
PA), Creighton; Christopher J. (San Diego, CA), Ho; Chih
Yung (Lansdale, PA), Huang; Yifang (Lansdale, PA),
Lu; Tianbao (Churchville, PA), Luo; Chi (New Hope,
PA), Reitz; Allen B. (Lansdale, PA), Reynolds; Charles
H. (Lansdale, PA), Ross; Tina Morgan (Royerford, PA),
Sieber-McMaster; Ellen (Langhorne, PA) |
Assignee: |
Janssen Pharmaceutica N.V.
(Beerse, BE)
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Family
ID: |
40488089 |
Appl.
No.: |
12/362,020 |
Filed: |
January 29, 2009 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20090227581 A1 |
Sep 10, 2009 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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61024244 |
Jan 29, 2008 |
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Current U.S.
Class: |
514/235.2;
544/128; 546/159; 514/313 |
Current CPC
Class: |
A61P
43/00 (20180101); C07D 405/06 (20130101); C07D
405/14 (20130101); A61P 25/00 (20180101); A61P
25/28 (20180101); C07D 409/14 (20130101); A61P
25/16 (20180101) |
Current International
Class: |
A61K
31/5377 (20060101); A61K 31/4709 (20060101); C07D
215/38 (20060101); C07D 413/14 (20060101) |
Field of
Search: |
;514/235.2,313 ;544/128
;546/159,160 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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406958 |
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Jan 1991 |
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EP |
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1407774 |
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Apr 2004 |
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EP |
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63-196573 |
|
Aug 1988 |
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JP |
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04 011255 |
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Jan 1992 |
|
JP |
|
01/38315 |
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May 2000 |
|
WO |
|
02/100399 |
|
Dec 2002 |
|
WO |
|
2004/022523 |
|
Mar 2004 |
|
WO |
|
2004/058686 |
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Jul 2004 |
|
WO |
|
2005/049585 |
|
Jun 2005 |
|
WO |
|
2006/017836 |
|
Feb 2006 |
|
WO |
|
2006/017844 |
|
Feb 2006 |
|
WO |
|
2006/024932 |
|
Mar 2006 |
|
WO |
|
2006/078577 |
|
Jul 2006 |
|
WO |
|
2007/050612 |
|
May 2007 |
|
WO |
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2007/092846 |
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Aug 2007 |
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WO |
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2007/092854 |
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Aug 2007 |
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WO |
|
Other References
Citron, Trends in Pharm. Sci., vol. 25, Issue 2, Feb. 2004, 92-97.
cited by other .
Cole, et al., Molecular Neurodegeneration 2007, 2:22. cited by
other .
Hamaguchi, et al., Cell. Mol. Life Sci. 63 (2006) 1538-1552. cited
by other .
Database Caplus "Online!" Chemical Abstracts Service, Columbus,
Ohio, US. Ishikawa, Fumyoshi et al.: "Quinazolineacetic acid
derivatives as platelet aggregation inhibitors". XP00236713. cited
by other .
El Mouedden, M. et al., (Johnson & Johnson Pharmaceutical
Research and Development, Division of Janssen Pharmaceutica N.V.,
Turnhoutseweg 30, Beerse, Belg.), Development of a specific ELISA
for the quantitative study of amino-terminally truncated
beta-amyloid peptides,. Journal of Neuroscience Methods (2005),
145(1-2), pp. 97-105. cited by other .
Ermolieff et al., Biochemistry, (2000) vol. 39, p. 12450. cited by
other .
Games, D. et al., (Athena Neurosciences, Inc., South San Francisco,
CA, USA), Alzheimer-type neuropathology in transgenic mice
overexpressing V717F .beta.-amyloid precursor protein, Nature
(London) (1995), 373(6514), pp. 523-527 (V717F mice). cited by
other .
Hsiao, K. et al., (Dep. Neurology, Univ. Minnesota, Minneapolis,
MN, USA), Correlative memory deficits, A.beta. elevation, and
amyloid plaques in transgenic mice, Science (Washington, D. C.)
(1996), 274(5284), pp. 99-102 (Tg2576 mice). cited by other .
Kienzle, F. et. al., Chemical Abstract, 1983, vol. 98, Abstract No.
143363, (or CAPLUS Accession No. 1983:143363). cited by other .
Kienzle, F., et al. "1,5-Dihydroimdazoquinazoliones as Blood
Platelet Aggregation Inhibitors", European Journal of Medicinal
Chemistry, 17(6), 547-556. cited by other .
Larner, A.J.: "Secretases as Therapeutic Targets in Alzheimer's
Disease: Patents 2000 2004". Expert Opinion On Therapeutic Patents,
Ashley Publications, GB, vol. 14, No. 10, 2004, pp. 1403-1420,
XP002404250. cited by other .
Lewczuk, P. et al., (Department of Psychiatry and Psychotherapy,
Molecular Neurobiology Lab, University of Erlangen-Nuremberg,
Erlangen, Germany), Neurochemical diagnosis of Alzheimer's dementia
by CSF A.beta.42, A.beta.42/A.beta.40 ratio and total tau,
Neurobiology of Aging (2004), 25(3), pp. 273-281. cited by other
.
Lins, H. et al., (Department of Neurology,
Otto-von-Guericke-University, Magdeburg, Germany),
Immunoreactivities of amyloid .beta. peptide(1-42) and total .tau.
C protein in lumbar cerebrospinal fluid of patients with normal
pressure hydrocephalus, Journal of Neural Transmission (2004),
111(3), pp. 273-280. cited by other .
Neve, R. L. et al., (Dep. Genetics, Harvard Medical School and
McLean Hospital, Belmont, MA, USA), Transgenic mice expressing
APP-C100 in the brain, Neurobiology of Aging (1996), 17(2), pp.
191-203 (APP-C100 mice). cited by other .
Oddo, S. et al, (Department of Neurobiology and Behavior,
University of California, Irvine, Irvine, CA, USA),
Triple-transgenic model of Alzheimer's disease with plaques and
tangles: Intracellular A.beta. and synaptic dysfunction, Neuron
(2003), 39(3), pp. 409-421 (APP Triple Transgenic Mice). cited by
other .
Olsson, A. et al., (Sahlgrenska University Hospital, Experimental
Neuroscience Section, Institute of Clinical Neuroscience, Goteborg
University, Moelndal, Sweden), Measurement of .alpha.- and
.beta.-secretase cleaved amyloid precursor protein in cerebrospinal
fluid from Alzheimer patients, Experimental Neurology (2003),
183(1), pp. 74-80. cited by other .
Ruberti et al., (Neuroscience Program, International School for
Advanced Studies (SISSA), Trieste, Italy), Phenotypic knockout of
nerve growth factor in adult transgenic mice reveals severe
deficits in basal forebrain cholinergic neurons, cell death in the
spleen, and skeletal muscle dystrophy, Journal of Neuroscience
(2000), 20(7), pp. 2589-2601 (AD11 mice). cited by other .
Schoonenboom, N.S. et al., Amyloid .beta. 38, 40, and 42 species in
cerebrospinal fluid: More of the same?, Annals of Neurology (2005),
58(1), pp. 139-142. cited by other .
Sirinathsinghji, D. J. S. (Merck Sharp and Dohme Research
Laboratories, Neuroscience Research Centre, Essex, UK.), Transgenic
mouse models of Alzheimer's disease, Biochemical Society
Transactions (1998), 26(3), pp. 504-508. cited by other .
Van Leuven, F. (Experimental Genetics Group, Center for Human
Genetics, Flemish Institute for Biotechnology (VIB), K.U.Leuven,
Louvain, Belg.), Single and multiple transgenic mice as models for
Alzheimer's disease, Progress in Neurobiology (Oxford) (2000),
61(3), pp. 305-312. cited by other .
Vanderstichele, H. et al., (Innogenetics NV, Ghent, Belg.),
Standardization of measurement of .beta.-amyloid(1-42) in
cerebrospinal fluid and plasma, Amyloid (2000), 7(4), pp. 245-258.
cited by other .
Venuti, M., et al. Inhibitors of Cyclic AMP Phosphodiestrase 2
Structural Variations of
N-Cyclohexyl-N-Methyl-4-(1,2,3,5-Tetrahydro-2-Oxoimidazo 2,1-B
Quinazo-7-yl-Oxybutyramids J. Medicinal Chemistry, American
Chemical Society, vol. 30, No. 2, 1987, pp. 303-318. cited by other
.
Wahlund, L.-O et al., (Karolinska Institute, Section of Geriatric
Medicine, Department of Clinical Neuroscience and Family Medicine,
Huddinge University Hospital, Stockholm, Sweden), Cerebrospinal
fluid biomarkers for disease stage and intensity in cognitively
impaired patients, Neuroscience Letters (2003), 339(2), pp. 99-102.
cited by other .
Webb, T. Improved Synthesis of Symmetrical and Unsymmetrical 5,11-
Methandibenzo'b.f.1,5-iazocines. Readily Available Inanoscale
Structural Units, Journal of Organic Chemistry, vol. 55, No. 1,
1990, pp. 363-365. cited by other .
Office Action mailed Jun. 19, 2009 in U.S. Appl. No. 11/671,681.
cited by other .
Office Action mailed Sep. 29, 2009 in U.S. Appl. No. 11/671,681.
cited by other .
Office Action mailed Jun. 19, 2008 in U.S. Appl. No. 11/671,703.
cited by other .
Office Action mailed Aug. 20, 2008 in U.S. Appl. No. 11/671,703.
cited by other .
Office Action mailed Feb. 12, 2009 in U.S. Appl. No. 11/671,703.
cited by other .
Office Action mailed Jun. 9, 2009 in U.S. Appl. No. 11/671,703.
cited by other .
Notice of Allowance mailed Nov. 19, 2009 in U.S. Appl. No.
11/671,703. cited by other .
Office Action mailed Mar. 24, 2009 in U.S. Appl. No. 11/671,732.
cited by other .
Notice of Allowance mailed Sep. 25, 2009 in U.S. Appl. No.
11/671,732. cited by other .
Notice of Allowance mailed Jan. 6, 2010 in U.S. Appl. No.
11/671,732. cited by other .
Office Action mailed Aug. 21, 2008 in U.S. Appl. No. 11/197,669.
cited by other .
Office Action mailed Apr. 29, 2009 in U.S. Appl. No. 11/197,669.
cited by other .
Notice of Allowance mailed Dec. 8, 2009 in U.S. Appl. No.
11/197,669. cited by other .
Office Action mailed May 30, 2008 in U.S. Appl. No. 11/197,608.
cited by other .
Office Action mailed Aug. 20, 2008 in U.S. Appl. No. 11/197,608.
cited by other .
Office Action mailed Apr. 30, 2009 in U.S. Appl. No. 11/197,608.
cited by other .
Notice of Allowance mailed Dec. 8, 2009 in U.S. Appl. No.
11/197,608. cited by other .
Office Action mailed May 29, 2008 in U.S. Appl. No. 11/197,615.
cited by other .
Office Action mailed Jan. 27, 2009 in U.S. Appl. No. 11/197,615.
cited by other.
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Primary Examiner: Saeed; Kamal A
Assistant Examiner: Bianchi; Kristin
Attorney, Agent or Firm: Woodrow; Hal Brent
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application
61/024,244 filed on Jan. 29, 2008, which is incorporated by
reference herein in its entirety.
Claims
We claim:
1. A compound of formula (I) ##STR00032## wherein a is an integer
from 0 to 4; R.sup.1 is selected from the group consisting of
halogen, C.sub.1-4alkyl, C.sub.1-4alkoxy, halogenated
C.sub.1-4alkyl and halogenated C.sub.1-4alkoxy; ##STR00033## is
selected from the group consisting of aryl and heteroaryl; R.sup.2
is selected from the group consisting of hydrogen and
C.sub.1-4alkoxy; R.sup.3 is selected from the group consisting of
hydrogen, C.sub.1-8alkyl, hydroxy substituted C.sub.2-8alkyl,
NR.sup.AR.sup.B substituted C.sub.2-8alkyl,
--C.sub.1-4alkyl-O--C.sub.1-4alkyl, cycloalkyl,
--(C.sub.1-4alkyl)-cycloalkyl, heterocycloalkyl and
--(C.sub.1-4alkyl)-heterocycloalkyl; wherein R.sup.A and R.sup.B
are each independently selected from the group consisting of
hydrogen and C.sub.1-4alkyl; A.sup.1 is selected from the group
consisting of --(CH.sub.2).sub.b--; wherein b is an integer from 2
to 4; L.sup.1 is selected from the group consisting of --NR.sup.C--
and --C(O)--NR.sup.C--; wherein R.sup.C is selected from the group
consisting of hydrogen, C.sub.1-8alkyl, hydroxy substituted
C.sub.1-4alkyl, --C.sub.1-4alkyl-O--C.sub.1-4alkyl and
C.sub.5-7cycloalkyl; R.sup.4 is selected from the group consisting
of C.sub.1-8alkyl, C.sub.2-12alkenyl,
--C.sub.1-4alkyl-O--C.sub.1-4alkyl,
--C.sub.1-4alkyl-NR.sup.DR.sup.E, --C.sub.1-4alkyl-OH, cycloalkyl,
--C.sub.1-4alkyl-cycloalkyl, partially unsaturated carbocyclyl,
--C.sub.1-4alkyl-(partially unsaturated carbocyclyl), aryl,
aralkyl, heteroaryl, --C.sub.1-4alkyl-heteroaryl, heterocycloalkyl
and --C.sub.1-4alkyl-heterocycloalkyl; wherein R.sup.D and R.sup.E
are each independently selected from the group consisting of
hydrogen and C.sub.1-4alkyl; and wherein the cycloalkyl, partially
unsaturated carbocyclyl, aryl, heteroaryl or heterocycloalkyl,
whether alone or as part of a substituent group, is optionally
substituted with one or more substituents independently selected
from the group consisting of fluoro, C.sub.1-4alkyl,
--C.sub.1-4alkyl-O--C.sub.1-4alkyl, carboxy,
--C(O)O--C.sub.1-4alkyl and aralkyl; alternatively, L.sup.1 is
--NR.sup.C-- and R.sup.C and R.sup.4 are taken together with the
nitrogen atom to which they are attached to form a ring structure
selected from the group consisting of 1-pyrazolyl, 1-imidazolyl and
1-(1,2,3-triazolyl); wherein the 1-pyrazolyl, 1-imidazolyl or
1-(1,2,3-triazolyl) is optionally substituted with a substituent
selected from the group consisting of C.sub.1-6alkyl; or a
pharmaceutically acceptable salt thereof.
2. A compound as in claim 1, wherein a is an integer from 0 to 3;
R.sup.1 is selected from the group consisting of halogen,
C.sub.1-4alkoxy, halogenated C.sub.1-4alkyl and halogenated
C.sub.1-4alkoxy; ##STR00034## is selected from the group consisting
of aryl and heteroaryl; R.sup.2 is selected from the group
consisting of hydrogen and C.sub.1-4alkoxy; R.sup.3 is selected
from the group consisting of C.sub.1-8alkyl, hydroxy substituted
C.sub.2-8alkyl, NR.sup.AR.sup.B substituted C.sub.2-8alkyl,
cycloalkyl, --(C.sub.1-4alkyl)-cycloalkyl, heterocycloalkyl and
--(C.sub.1-4alkyl)-heterocycloalkyl; wherein R.sup.A and R.sup.B
are each independently selected from the group consisting of
hydrogen and C.sub.1-4alkyl; A.sup.1 is selected from the group
consisting of --(CH.sub.2).sub.b--; wherein b is an integer from 2
to 4; L.sup.1 is selected from the group consisting of --NR.sup.C--
and --C(O)--NR.sup.C--; wherein R.sup.C is selected from the group
consisting of hydrogen, C.sub.1-8alkyl, hydroxy substituted
C.sub.1-4alkyl and C.sub.5-7cycloalkyl; R.sup.4 is selected from
the group consisting of C.sub.1-8alkyl,
--C.sub.1-4alkyl-O--C.sub.1-4alkyl,
--C.sub.1-4alkyl-NR.sup.DR.sup.E, --C.sub.1-4alkyl-OH, cycloalkyl,
--C.sub.1-4alkyl-cycloalkyl, aryl, aralkyl, heteroaryl,
--C.sub.1-4alkyl-heteroaryl, heterocycloalkyl and
--C.sub.1-4alkyl-heterocycloalkyl; wherein R.sup.D and R.sup.E are
each independently selected from the group consisting of hydrogen
and C.sub.1-4alkyl; and wherein the cycloalkyl, partially
unsaturated carbocyclyl, aryl, heteroaryl or heterocycloalkyl,
whether alone or as part of a substituent group, is optionally
substituted with one or more substituents independently selected
from the group consisting of fluoro, C.sub.1-4alkyl, carboxy,
--C(O)O--C.sub.1-4alkyl and aralkyl; alternatively, L.sup.1 is
--NR.sup.C-- and R.sup.C and R.sup.4 are taken together with the
nitrogen atom to which they are attached to form a ring structure
selected from the group consisting of 1-pyrazolyl, 1-imidazolyl and
1-(1,2,3-triazolyl); wherein the 1-pyrazolyl, 1-imidazolyl or
1-(1,2,3-triazolyl) is optionally substituted with a substituent
selected from the group consisting of C.sub.1-6alkyl; or a
pharmaceutically acceptable salt thereof.
3. A compound as in claim 2, wherein a is an integer from 0 to 2;
R.sup.1 is selected from the group consisting of halogen,
C.sub.1-2alkoxy, fluorinated C.sub.1-2alkyl and fluorinated
C.sub.1-2alkoxy; ##STR00035## is selected from the group consisting
of aryl and heteroaryl; R.sup.2 is selected from the group
consisting of hydrogen and C.sub.1-2alkoxy; R.sup.3 is selected
from the group consisting of cycloalkyl and heterocycloalkyl;
A.sup.1 is selected from the group consisting of
--(CH.sub.2).sub.b; wherein b is an integer from 2 to 3; L.sup.1 is
selected from the group consisting of --NR.sup.C-- and
--C(O)--NR.sup.C--; wherein R.sup.C is selected from the group
consisting of hydrogen, C.sub.1-8alkyl and cycloalkyl; R.sup.4 is
selected from the group consisting of C.sub.1-8alkyl, hydroxy
substituted C.sub.1-6alkyl, --C.sub.1-4alkyl-O--C.sub.1-4alkyl-,
cycloalkyl, --C.sub.1-2alkyl-cycloalkyl, aralkyl, heteroaryl,
--C.sub.1-2alkyl-heteroaryl and --C.sub.1-2alkyl-heterocycloalkyl;
wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl,
whether alone or as part of a substituted group is optionally
substituted with C.sub.1-4alkyl; alternatively, L.sup.1 is
--NR.sup.C-- and R.sup.C and R.sup.4 are taken together with the
nitrogen atom to which they are bound to form 1-(1,2,3-triazolyl);
wherein the 1,2,3-triazolyl is optionally substituted with a
C.sub.1-4alkyl; or a pharmaceutically acceptable salt thereof.
4. A compound as in claim 3, wherein a is an integer from 0 to 2;
R.sup.1 is selected from the group consisting of fluoro, methoxy,
ethoxy, trifluoromethyl and trifluoromethoxy; ##STR00036## is
selected from the group consisting of phenyl, 2-thienyl,
2-pyrrolyl, 2-pyridyl and 7-indolyl; R.sup.2 is selected from the
group consisting of hydrogen, methoxy and ethoxy; R.sup.3 is
selected from the group consisting of (S)-cyclohexyl and
4-tetrahydropyranyl; A.sup.1 is selected from the group consisting
of --CH.sub.2CH.sub.2-- and --CH.sub.2CH.sub.2CH.sub.2--; L.sup.1
is selected from the group consisting of --NR.sup.C-- and
--C(O)--NR.sup.C--; wherein R.sup.C is selected from the group
consisting of hydrogen, methyl, 3,3-dimethyl-n-butyl and
cyclohexyl; R.sup.4 is selected from the group consisting of
1-(3,3,-dimethyl-n-butyl), 1-hydroxy-ethyl-,
1-(2,2-dimethyl-3-hydroxy-n-propyl), t-butoxy-ethyl, cyclohexyl,
1-adamantyl, cyclopropyl-methyl-, cyclohexyl-methyl-, benzyl,
2-(1-methyl-imidazolyl), 2-pyridyl-methyl-, 1-pyrrolidinyl-ethyl-,
5-thiazolyl-methyl- and 4-morpholinyl-ethyl-; alternatively,
L.sup.1 is --NR.sup.C-- and R.sup.C and R.sup.4 are taken together
with the nitrogen atom to which they are bound to form
1-(4-t-butyl-1,2,3-triazolyl); or a pharmaceutically acceptable
salt thereof.
5. A compound as in claim 4, wherein a is an integer from 1 to 2;
R.sup.1 is selected from the group consisting of fluoro, methoxy
and ethoxy; ##STR00037## is selected from the group consisting of
phenyl and 2-thienyl; R.sup.2 is selected from the group consisting
of hydrogen, methoxy and ethoxy; R.sup.3 is 4-tetrahydropyranyl;
A.sup.1 is selected from the group consisting of
--CH.sub.2CH.sub.2-- and --CH.sub.2CH.sub.2CH.sub.2--; L.sup.1 is
selected from the group consisting of --NR.sup.C-- and
--C(O)--NR.sup.C--; wherein R.sup.C is selected from the group
consisting of hydrogen, 3,3-dimethyl-n-butyl and cyclohexyl;
R.sup.4 is selected from the group consisting of
1-(3,3-dimethyl-n-butyl), t-butoxy-ethyl, 1-adamantyl,
cyclohexyl-methyl-, benzyl, 2-(1-methyl-imidazolyl),
2-pyridyl-methyl-, 1-pyrrolidinyl-ethyl-, 5-thiazolyl-methyl- and
4-morpholinyl-ethyl-; alternatively, L.sup.1 is --NR.sup.C-- and
R.sup.C and R.sup.4 are taken together with the nitrogen atom to
which they are bound to form 1-(4-t-butyl-1,2,3-triazolyl); or a
pharmaceutically acceptable salt thereof.
6. A compound as in claim 4, wherein a is an integer from 1 to 2;
R.sup.1 is selected from the group consisting of fluoro and ethoxy;
##STR00038## is selected from the group consisting of phenyl and
2-thienyl; R.sup.2 is hydrogen; R.sup.3 is 4-tetrahydropyranyl;
A.sup.1 is --CH.sub.2CH.sub.2--; L.sup.1 is --C(O)--NR.sup.C--;
wherein R.sup.C is selected from the group consisting of hydrogen,
3,3-dimethyl-n-butyl and cyclohexyl; R.sup.4 is selected from the
group consisting of 1-(3,3-dimethyl-n-butyl), cyclohexyl-methyl-,
benzyl, 2-(1-methyl-imidazolyl), 2-pyridyl-methyl-,
1-pyrrolidinyl-ethyl-, 5-thiazolyl-methyl- and
4-morpholinyl-ethyl-; or a pharmaceutically acceptable salt
thereof.
7. A compound as in claim 4, wherein a is 1; R.sup.1 is selected
from the group consisting of fluoro, methoxy and trifluoromethoxy;
##STR00039## is selected from the group consisting of phenyl,
2-thienyl and 7-indolyl; R.sup.2 is selected from the group
consisting of hydrogen and ethoxy; R.sup.3 is 4-tetrahydropyranyl;
A.sup.1 is selected from the group consisting of
--CH.sub.2CH.sub.2-- and --CH.sub.2CH.sub.2CH.sub.2--; L.sup.1 is
selected from the group consisting of --NR.sup.C-- and
--C(O)--NR.sup.C--; wherein R.sup.C is selected from the group
consisting of hydrogen, methyl and 3,3-dimethyl-n-butyl; R.sup.4 is
selected from the group consisting of 1-(3,3,-dimethyl-n-butyl),
1-adamantyl, cyclohexyl-methyl-, 2-(1-methyl-imidazolyl),
5-thiazolyl-methyl- and 4-morpholinyl-ethyl-; alternatively,
L.sup.1 is --NR.sup.C-- and R.sup.C and R.sup.4 are taken together
with the nitrogen atom to which they are bound to form
1-(4-t-butyl-1,2,3-triazolyl); or a pharmaceutically acceptable
salt thereof.
8. A compound as in claim 4, wherein a is 1; R.sup.1 is selected
from the group consisting of fluoro, methoxy and trifluoromethoxy;
##STR00040## is selected from the group consisting of phenyl and
7-indolyl; R.sup.2 is hydrogen; R.sup.3 is 4-tetrahydropyranyl;
A.sup.1 is selected from the group consisting of
--CH.sub.2CH.sub.2-- and --CH.sub.2CH.sub.2CH.sub.2--; L.sup.1 is
selected from the group consisting of --NR.sup.C-- and
--C(O)--NR.sup.C--; wherein R.sup.C is selected from the group
consisting of hydrogen, methyl and 3,3-dimethyl-n-butyl; R.sup.4 is
selected from the group consisting of 1-(3,3,-dimethyl-n-butyl),
1-adamantyl, cyclohexyl-methyl-, 2-(1-methyl-imidazolyl),
5-thiazolyl-methyl- and 4-morpholinyl-ethyl-; or a pharmaceutically
acceptable salt thereof.
9. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound of claim 1.
10. A pharmaceutical composition made by mixing a compound of claim
1 and a pharmaceutically acceptable carrier.
11. A process for making a pharmaceutical composition comprising
mixing a compound of claim 1 and a pharmaceutically acceptable
carrier.
Description
FIELD OF THE INVENTION
The present invention is directed to novel 2-amino-quinoline
derivatives, pharmaceutical compositions containing them and their
use in the treatment of Alzheimer's disease (AD), mild cognitive
impairment, senility and/or dementia. The compounds of the present
invention are inhibitors of .beta.-secretase, also known as
.beta.-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin
2.
BACKGROUND OF THE INVENTION
Alzheimer's Disease (AD) is a neurodegenerative disease associated
with aging. AD patients suffer from cognition deficits and memory
loss as well as behavioral problems such as anxiety. Over 90% of
those afflicted with AD have a sporadic form of the disorder while
less than 10% of the cases are familial or hereditary. In the
United States, about 1 in 10 people at age 65 have AD while at age
85, 1 out of every two individuals are affected with AD. The
average life expectancy from the initial diagnosis is 7-10 years,
and AD patients require extensive care either in an assisted living
facility which is very costly or by family members. With the
increasing number of elderly in the population, AD is a growing
medical concern. Currently available therapies for AD merely treat
the symptoms of the disease and include acetylcholinesterase
inhibitors to improve cognitive properties as well as anxiolytics
and antipsychotics to control the behavioral problems associated
with this ailment.
The hallmark pathological features in the brain of AD patients are
neurofibillary tangles which are generated by hyperphosphorylation
of tau protein and amyloid plaques which form by aggregation of
.beta.-amyloid.sub.1-42 (A.beta..sub.1-42) peptide.
A.beta..sub.1-42 forms oligomers and then fibrils, and ultimately
amyloid plaques. The oligomers and fibrils are believed to be
especially neurotoxic and may cause most of the neurological damage
associated with AD. Agents that prevent the formation of
A.beta..sub.1-42 have the potential to be disease-modifying agents
for the treatment of AD. A.beta..sub.1-42 is generated from the
amyloid precursor protein (APP), comprised of 770 amino acids. The
N-terminus of A.beta..sub.1-42 is cleaved by .beta.-secretase
(BACE), and then .gamma.-secretase cleaves the C-terminal end. In
addition to A.beta..sub.1-42, .gamma.-secretase also liberates
A.beta..sub.1-40 which is the predominant cleavage product as well
as A.beta..sub.1-38 and A.beta..sub.1-43. These A.beta. forms can
also aggregate to form oligomers and fibrils. Thus, inhibitors of
BACE would be expected to prevent the formation of A.beta..sub.1-42
as well as A.beta..sub.1-40, A.beta..sub.1-38 and A.beta..sub.1-43
and would be potential therapeutic agents in the treatment of
AD.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of formula (I)
##STR00001##
wherein
a is an integer from 0 to 4;
R.sup.1 is selected from the group consisting of halogen,
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogenated C.sub.1-4alkyl and
halogenated C.sub.1-4alkoxy;
##STR00002## is selected from the group consisting of aryl and
heteroaryl;
R.sup.2 is selected from the group consisting of hydrogen and
C.sub.1-4alkoxy;
R.sup.3 is selected from the group consisting of hydrogen,
C.sub.1-8alkyl, hydroxy substituted C.sub.2-8alkyl, NR.sup.AR.sup.B
substituted C.sub.2-8alkyl, --C.sub.1-4alkyl-O--C.sub.1-4alkyl,
cycloalkyl, --(C.sub.1-4alkyl)-cycloalkyl, heterocycloalkyl and
--(C.sub.1-4alkyl)-heterocycloalkyl; wherein R.sup.A and R.sup.B
are each independently selected from the group consisting of
hydrogen and C.sub.1-4alkyl;
A.sup.1 is selected from the group consisting of
--(CH.sub.2).sub.b--; wherein b is an integer from 2 to 4;
L.sup.1 is selected from the group consisting of --NR.sup.C-- and
--C(O)--NR.sup.C--; wherein R.sup.C is selected from the group
consisting of hydrogen, C.sub.1-8alkyl, hydroxy substituted
C.sub.1-4alkyl, --C.sub.1-4alkyl-O--C.sub.1-4alkyl and
C.sub.5-7cycloalkyl;
R.sup.4 is selected from the group consisting of C.sub.1-8alkyl,
C.sub.2-12alkenyl, --C.sub.1-4alkyl-O--C.sub.1-4alkyl,
--C.sub.1-4alkyl-NR.sup.DR.sup.E, --C.sub.1-4alkyl-OH, cycloalkyl,
--C.sub.1-4alkyl-cycloalkyl, partially unsaturated carbocyclyl,
--C.sub.1-4alkyl-(partially unsaturated carbocyclyl), aryl,
aralkyl, heteroaryl, --C.sub.1-4alkyl-heteroaryl, heterocycloalkyl
and --C.sub.1-4alkyl-heterocycloalkyl;
wherein R.sup.D and R.sup.E are each independently selected from
the group consisting of hydrogen and C.sub.1-4alkyl;
and wherein the cycloalkyl, partially unsaturated carbocyclyl,
aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a
substituent group, is optionally substituted with one or more
substituents independently selected from the group consisting of
fluoro, C.sub.1-4alkyl, --C.sub.1-4alkyl-O--C.sub.1-4alkyl,
carboxy, --C(O)O--C.sub.1-4alkyl and aralkyl;
alternatively, L.sup.1 is --NR.sup.C-- and R.sup.C and R.sup.4 are
taken together with the nitrogen atom to which they are attached to
form a ring structure selected from the group consisting of
1-pyrazolyl, 1-imidazolyl and 1-(1,2,3-triazolyl); wherein the
1-pyrazolyl, 1-imidazolyl or 1-(1,2,3-triazolyl) is optionally
substituted with a substituent selected from the group consisting
of C.sub.1-6alkyl;
and pharmaceutically acceptable salts thereof.
Illustrative of the invention is a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and any of the
compounds described above. An illustration of the invention is a
pharmaceutical composition made by mixing any of the compounds
described above and a pharmaceutically acceptable carrier.
Illustrating the invention is a process for making a pharmaceutical
composition comprising mixing any of the compounds described above
and a pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating a disorder
mediated by the .beta.-secretase enzyme, comprising administering
to a subject in need thereof a therapeutically effective amount of
any of the compounds or pharmaceutical compositions described
above.
Further exemplifying the invention are methods of inhibiting the
.beta.-secretase enzyme, comprising administering to a subject in
need thereof a therapeutically effective amount of any of the
compounds or pharmaceutical compositions described above.
An example of the invention is a method of treating a disorder
selected from the group consisting of Alzheimer's disease (AD),
mild cognitive impairment, senility, dementia, dementia with Lewy
bodies, Down's syndrome, dementia associated with stroke, dementia
associated with Parkinson's disease and dementia associated with
beta-amyloid, preferably Alzheimer's disease, comprising
administering to a subject in need thereof, a therapeutically
effective amount of any of the compounds or pharmaceutical
compositions described above.
Another example of the invention is the use of any of the compounds
described above in the preparation of a medicament for treating:
(a) Alzheimer's Disease (AD), (b) mild cognitive impairment, (c)
senility, (d) dementia, (e) dementia with Lewy bodies, (f) Down's
syndrome, (g) dementia associated with stroke, (h) dementia
associated with Parkinson's disease and (i) dementia associated
with beta-amyloid, in a subject in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of formula (I)
##STR00003##
wherein a, R.sup.1,
##STR00004## R.sup.2, R.sup.3, A.sup.1, L.sup.1 and R.sup.4 are as
herein defined, and pharmaceutically acceptable salts thereof. The
compounds of formula (I) are inhibitors of the .beta.-secretase
enzyme (also known as .beta.-site cleaving enzyme, BACE, BACE1,
Asp2 or memapsin 2), and are useful in the treatment of Alzheimer's
disease (AD), mild cognitive impairment (MCI), senility, dementia,
dementia associated with stroke, dementia with Lewy bodies, Down's
syndrome, dementia associated with Parkinson's disease and dementia
associated with beta-amyloid, preferably Alzheimer's disease, mild
cognitive impairment or dementia, more preferably Alzheimer's
disease.
In an embodiment of the present invention, a is an integer from 0
to 3. In another embodiment of the present invention, a is an
integer from 0 to 2. In another embodiment of the present
invention, a is an integer from 1 to 2. In another embodiment of
the present invention, a is 1.
In an embodiment of the present invention, R.sup.1 is selected from
the group consisting of halogen, C.sub.1-4alkoxy, halogenated
C.sub.1-4alkyl and halogenated C.sub.1-4alkoxy. In another
embodiment of the present invention, R.sup.1 is selected from the
group consisting of halogen, C.sub.1-2alkoxy, fluorinated
C.sub.1-2alkyl and fluorinated C.sub.1-2alkoxy.
In another embodiment of the present invention, R.sup.1 is selected
from the group consisting of fluoro, methoxy, ethoxy,
trifluoromethyl and trifluoromethoxy. In another embodiment of the
present invention, R.sup.1 is selected from the group consisting of
fluoro, methoxy and ethoxy. In another embodiment of the present
invention, R.sup.1 is selected from the group consisting of fluoro
and ethoxy. In another embodiment of the present invention, R.sup.1
is selected from the group consisting of fluoro, methoxy and
trifluoromethoxy.
In an embodiment of the present invention,
##STR00005## is selected from the group consisting of aryl and
heteroaryl. In another embodiment of the present invention,
##STR00006## is selected from the group consisting of phenyl,
2-thienyl, 2-pyrrolyl, 2-pyridyl and 7-indolyl. In another
embodiment of the present invention,
##STR00007## is selected from the group consisting of phenyl and
2-thienyl. In another embodiment of the present invention,
##STR00008## is selected from the group consisting of phenyl,
2-thienyl and 7-indolyl. In another embodiment of the present
invention,
##STR00009## is selected from the group consisting of phenyl and
7-indolyl.
In an embodiment of the present invention, R.sup.2 is selected from
the group consisting of hydrogen and C.sub.1-4alkoxy. In another
embodiment of the present invention, R.sup.2 is selected from the
group consisting of hydrogen and C.sub.1-2alkoxy. In another
embodiment of the present invention, R.sup.2 is selected from the
group consisting of hydrogen, methoxy and ethoxy. In another
embodiment of the present invention, R.sup.2 is hydrogen. In
another embodiment of the present invention, R.sup.2 is selected
from the group consisting of hydrogen and ethoxy.
In an embodiment of the present invention, R.sup.3 is selected from
the group consisting of C.sub.1-8alkyl, hydroxy substituted
C.sub.2-8alkyl, NR.sup.AR.sup.B substituted C.sub.2-8alkyl,
cycloalkyl, --(C.sub.1-4alkyl)-cycloalkyl, heterocycloalkyl and
--(C.sub.1-4alkyl)-heterocycloalkyl; wherein R.sup.A and R.sup.B
are each independently selected from the group consisting of
hydrogen and C.sub.1-4alkyl. In another embodiment of the present
invention, R.sup.3 is selected from the group consisting of
cycloalkyl and heterocycloalkyl. In another embodiment of the
present invention, R.sup.3 is selected from the group consisting of
(S)-cyclohexyl and 4-tetrahydropyranyl. In another embodiment of
the present invention, R.sup.3 is 4-tetrahydropyranyl.
In an embodiment of the present invention, A.sup.1 is selected from
the group consisting of --(CH.sub.2).sub.b--; wherein b is an
integer from 2 to 4. In another embodiment of the present
invention, A.sup.1 is selected from the group consisting of
--(CH.sub.2).sub.b; wherein b is an integer from 2 to 3. In another
embodiment of the present invention, A.sup.1 is selected from the
group consisting of --CH.sub.2CH.sub.2-- and
--CH.sub.2CH.sub.2CH.sub.2--. In another embodiment of the present
invention, A.sup.1 is --CH.sub.2CH.sub.2--.
In an embodiment of the present invention, L.sup.1 is selected from
the group consisting of --NR.sup.C-- and --C(O)--NR.sup.C--. In
another embodiment of the present invention, L.sup.1 is
--C(O)--NR.sup.C--.
In an embodiment of the present invention, R.sup.C is selected from
the group consisting of hydrogen, C.sub.1-8alkyl, hydroxy
substituted C.sub.1-4alkyl and C.sub.5-7cycloalkyl. In another
embodiment of the present invention, R.sup.C is selected from the
group consisting of hydrogen, C.sub.1-8alkyl and cycloalkyl. In
another embodiment of the present invention, R.sup.C is selected
from the group consisting of hydrogen, methyl, 3,3-dimethyl-n-butyl
and cyclohexyl. In another embodiment of the present invention,
R.sup.C is selected from the group consisting of hydrogen,
3,3-dimethyl-n-butyl and cyclohexyl. In another embodiment of the
present invention, R.sup.C is selected from the group consisting of
hydrogen, methyl and 3,3-dimethyl-n-butyl.
In an embodiment of the present invention, R.sup.4 is selected from
the group consisting of C.sub.1-8alkyl,
--C.sub.1-4alkyl-O--C.sub.1-4alkyl,
--C.sub.1-4alkyl-NR.sup.DR.sup.E, --C.sub.1-4alkyl-OH, cycloalkyl,
--C.sub.1-4alkyl-cycloalkyl, aryl, aralkyl, heteroaryl,
--C.sub.1-4alkyl-heteroaryl, heterocycloalkyl and
--C.sub.1-4alkyl-heterocycloalkyl; wherein the cycloalkyl,
partially unsaturated carbocyclyl, aryl, heteroaryl or
heterocycloalkyl, whether alone or as part of a substituent group,
is optionally substituted with one or more substituents
independently selected from the group consisting of fluoro,
C.sub.1-4alkyl, carboxy, --C(O)O--C.sub.1-4alkyl and aralkyl; and
wherein R.sup.D and R.sup.E are each independently selected from
the group consisting of hydrogen and C.sub.1-4alkyl. In another
embodiment of the present invention, R.sup.4 is selected from the
group consisting of C.sub.1-8alkyl, hydroxy substituted
C.sub.1-6alkyl, --C.sub.1-4alkyl-O--C.sub.1-4alkyl-, cycloalkyl,
--C.sub.1-2alkyl-cycloalkyl, aralkyl, heteroaryl,
--C.sub.1-2alkyl-heteroaryl and --C.sub.1-2alkyl-heterocycloalkyl;
wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl,
whether alone or as part of a substituted group is optionally
substituted with C.sub.1-4alkyl.
In another embodiment of the present invention, R.sup.4 is selected
from the group consisting of 1-(3,3,-dimethyl-n-butyl),
1-hydroxy-ethyl-, 1-(2,2-dimethyl-3-hydroxy-n-propyl),
t-butoxy-ethyl, cyclohexyl, 1-adamantyl, cyclopropyl-methyl-,
cyclohexyl-methyl-, benzyl, 2-(1-methyl-imidazolyl),
2-pyridyl-methyl-, 1-pyrrolidinyl-ethyl-, 5-thiazolyl-methyl- and
4-morpholinyl-ethyl-. In another embodiment of the present
invention, R.sup.4 is selected from the group consisting of
1-(3,3-dimethyl-n-butyl), t-butoxy-ethyl, 1-adamantyl,
cyclohexyl-methyl-, benzyl, 2-(1-methyl-imidazolyl),
2-pyridyl-methyl-, 1-pyrrolidinyl-ethyl-, 5-thiazolyl-methyl- and
4-morpholinyl-ethyl-. In another embodiment of the present
invention, R.sup.4 is selected from the group consisting of
1-(3,3-dimethyl-n-butyl), cyclohexyl-methyl-, benzyl,
2-(1-methyl-imidazolyl), 2-pyridyl-methyl-, 1-pyrrolidinyl-ethyl-,
5-thiazolyl-methyl- and 4-morpholinyl-ethyl-. In another embodiment
of the present invention, R.sup.4 is selected from the group
consisting of 1-(3,3,-dimethyl-n-butyl), 1-adamantyl,
cyclohexyl-methyl-, 2-(1-methyl-imidazolyl), 5-thiazolyl-methyl-
and 4-morpholinyl-ethyl-.
In an embodiment of the present invention, L.sup.1 is --NR.sup.C--
and R.sup.C and R.sup.4 are taken together with the nitrogen atom
to which they are attached to form a ring structure selected from
the group consisting of 1-pyrazolyl, 1-imidazolyl and
1-(1,2,3-triazolyl); wherein the 1-pyrazolyl, 1-imidazolyl or
1-(1,2,3-triazolyl) is optionally substituted with a substituent
selected from the group consisting of C.sub.1-6alkyl. In another
embodiment of the present invention, L.sup.1 is --NR.sup.C-- and
R.sup.C and R.sup.4 are taken together with the nitrogen atom to
which they are bound to form 1-(1,2,3-triazolyl); wherein the
1,2,3-triazolyl is optionally substituted with a C.sub.1-4alkyl. In
another embodiment of the present invention, L.sup.1 is
--NR.sup.C-- and R.sup.C and R.sup.4 are taken together with the
nitrogen atom to which they are bound to form
1-(4-t-butyl-1,2,3-triazolyl).
Additional embodiments of the present invention, include those
wherein the substituents selected for one or more of the variables
defined herein (i.e. a, R.sup.1,
##STR00010## R.sup.2, R.sup.3, A.sup.1, L.sup.1 and R.sup.4) are
independently selected to be any individual substituent or any
subset of substituents selected from the complete list as defined
herein. In another embodiment of the present invention is any
single compound or subset of compounds selected from the
representative compounds listed in Tables 1-2 below.
Representative compounds of the present invention are as listed in
Table 1 to 2 below. Unless otherwise noted, wherein a stereogenic
center is present in the listed compound, the compound was prepared
as a mixture of stereo-configurations. Where a stereogenic center
is present, the (S)- and (R)-designations are intended to indicate
that the exact stereo-configuration of the center has not been
determined.
TABLE-US-00001 TABLE 1 Representative Compounds of Formula (I)
##STR00011## ID No. ##STR00012## R.sup.2 R.sup.3 b L.sup.1 R.sup.4
1 2-fluoro- H 4-tetrahydro- 2 --C(O)--NH-- hydroxy-ethyl- phenyl
pyranyl 2 2-fluoro- H 4-tetrahydro- 2 --C(O)--NH-- cyclopropyl-
phenyl pyranyl methyl- 3 2-fluoro- H 4-tetrahydro- 3
--N(CH.sub.3)-- cyclopropyl- phenyl pyranyl methyl- 4 2-fluoro- H
4-tetrahydro- 2 --C(O)--N(CH.sub.3)-- cyclopropyl- phenyl pyranyl
methyl- 5 2-fluoro- H 4-tetrahydro- 3 --NH-- 1-(3,3- phenyl pyranyl
dimethyl-n- butyl) 6 2-fluoro- H 4-tetrahydro- 3 --NH-- 1-(2,2-
phenyl pyranyl dimethyl-3- hydroxy-n- propyl) 7 2-fluoro- H
4-tetrahdyro- 2 --C(O)--NH-- 1-(3,3- phenyl pyranyl dimethyl-n-
butyl) 8 2-fluoro- H 4-tetrahydro- 3 --N(CH.sub.3)-- 1-(3,3- phenyl
pyranyl dimethyl-n- butyl) 9 2-fluoro- H 4-tetrahydro- 2
--C(O)--NH-- 1-(2,2- phenyl pyranyl dimethyl-3- hydroxy-n- propyl)
10 2-fluoro- H 4-tetrahydro- 3 --NH-- t-butoxy-ethyl- phenyl
pyranyl 11 2-fluoro H (S)- 2 --C(O)--N(CH.sub.3)-- cyclohexyl
phenyl cyclohexyl 12 2-fluoro- H 4-tetrahydro- 2 --C(O)--NH--
cyclohexyl- phenyl pyranyl methyl- 13 2-fluoro- H 4-tetrahydro- 3
--N(CH.sub.3)-- cyclohexyl- phenyl pyranyl methyl- 14 2-fluoro- H
4-tetrahydro- 2 --C(O)--N(CH.sub.3)-- 1-(3,3- phenyl pyranyl
dimethyl-n- butyl) 15 2-fluoro- H 4-tetrahydro- 2 --C(O)--NH--
t-butoxy-ethyl- phenyl pyranyl 16 2-fluoro- --OCH.sub.3
4-tetrahydro- 3 --NH-- 1-(3,3- phenyl pyranyl dimethyl-n- butyl) 18
2-fluoro- H 4-tetrahydro- 2 --C(O)--N(CH.sub.3)-- cyclohexyl-
phenyl pyranyl methyl- 19 2-fluoro- --OCH.sub.3 4-tetrahydro- 2
--C(O)--NH-- 1-(3,3- phenyl pyranyl dimethyl-n- butyl) 21 2-thienyl
H 4-tetrahydro- 2 --C(O)--NH-- 1-adamantyl pyranyl 23 2-fluoro- H
4-tetrahydro- 2 --C(O)--NH-- 1-adamantyl phenyl pyranyl 24
2-pyrrolyl H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).su- b.3)-- 2-(1-methyl-
pyranyl imidazolyl) 25 phenyl H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub.3)- -- 2-(1-methyl-
pyranyl imidazolyl) 26 2-fluoro- H 4-tetrahydro- 3
--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub.3)-- - benzyl phenyl pyranyl
27 2-pyridyl H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- 2-(1-methyl-
pyranyl imidazolyl) 28 2-fluoro- H 4-tetrahydro- 3
--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub.3)-- - 2-pyridyl- phenyl
pyranyl methyl- 29 2-fluoro- H 4-tetrahydro- 3
--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub.3)-- - 2-(1-methyl- phenyl
pyranyl imidazolyl) 30 2-fluoro- H 4-tetrahydro- 3 --N(cyclohexyl)-
1-pyrrolidinyl- phenyl pyranyl ethyl 31 2-thienyl H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- 2-(1-methyl-
pyranyl imidazolyl 33 2-fluoro- H 4-tetrahydro- 3
--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub.3)-- - 5-thiazolyl phenyl
pyranyl methyl- 34 2-fluoro- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- benzyl phenyl
pyranyl 35 2-fluoro- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- 2-pyridyl-
phenyl pyranyl methyl 36 2-methoxy- H 4-tetrahydro- 3
--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub.3)--- 2-(1-methyl- phenyl
pyranyl imidazolyl) 37 4-fluoro- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- 2-(1-methyl-
phenyl pyranyl imidazolyl) 38 3-fluoro- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- 2-(1-methyl-
phenyl pyranyl imidazolyl) 39 2-fluoro- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- 2-(1-methyl-
phenyl pyranyl imidazolyl) 41 2-fluoro- H 4-tetrahydro- 2
--C(O)--N(cyclohexyl) 1-pyrrolidinyl- phenyl pyranyl ethyl- 42
2-fluoro- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- 5-thiazolyl
phenyl pyranyl methyl- 43 2-fluoro- H 4-tetrahydro- 3
--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub.3)-- - 4-morpholinyl- phenyl
pyranyl ethyl- 45 2-methoxy- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).su- b.3)-- 2-(1-methyl-
phenyl pyranyl imidazolyl) 46 2,4- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub.3)--- 2-(1-methyl-
phenyl pyranyl imidazolyl) 47 2-fluoro- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- 4-morpholinyl-
phenyl pyranyl ethyl- 49 7-indolyl H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- 2-(1-methyl-
pyranyl imidazolyl) 50 4-ethoxy- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- 2-(1-methyl-
phenyl pyranyl imidazolyl) 51 2-ethoxy- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).sub- .3)-- 2-(1-methyl-
phenyl pyranyl imidazolyl) 52 2-fluoro- --OCH.sub.3 4-tetrahydro- 3
--N(cyclohexyl)- 4-morpholinyl- phenyl pyranyl ethyl- 53 2-fluoro-
--OCH.sub.3 4-tetrahydro- 2 --C(O)--N(cyclohexyl)- 4-morpholi- nyl-
phenyl pyranyl ethyl- 54 3-trifluoro- H 4-tetrahydro- 2
--C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).- sub.3)-- 2-(1-methyl-
methyl- pyranyl imidazolyl) phenyl 55 2-trifluoro- H 4-tetrahydro-
2 --C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).- sub.3)-- 2-(1-methyl-
methyl- pyranyl imidazolyl) phenyl 56 2-trifluoro- H 4-tetrahydro-
2 --C(O)--N(CH.sub.2CH.sub.2--C(CH.sub.3).- sub.3)-- 2-(1-methyl-
methoxy- pyranyl imidazolyl) phenyl
TABLE-US-00002 TABLE 2 Representative Compounds of Formula (I)
##STR00013## ID No. ##STR00014## R.sup.2 R.sup.3 A.sup.1
-L.sup.1-R.sup.4 is --NR.sup.C--R.sup.4 where R.sup.C and R.sup.4
are taken together 17 2-fluoro- --OCH.sub.3 4-tetrahydro-
--CH.sub.2CH.sub.2-- 1-(4-t-butyl-1- ,2,3- phenyl pyranyl
triazolyl) 20 2-methoxy- --OCH.sub.3 4-tetrahydro-
--CH.sub.2CH.sub.2-- 1-(4-t-butyl-- 1,2,3- phenyl pyranyl
triazolyl) 22 2-fluoro- --OCH.sub.2--CH.sub.3 4-tetrahydro-
--CH.sub.2CH.sub.2-- 1-(4- -t-butyl-1,2,3- phenyl pyranyl
triazolyl)
As used herein, unless otherwise noted, the term "halogen" shall
mean chlorine, bromine, fluorine and iodine. Preferably, the
halogen is fluoro or chloro. More preferably, the halogen is
fluoro.
As used herein, unless otherwise noted, the term "alkyl" whether
used alone or as part of a substituent group, include straight and
branched chains. For example, alkyl radicals include methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,
n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, and the
like. Similarly, the term "C.sub.1-8alkyl" shall include straight
and branched chains comprising one to eight carbon atoms.
As used herein, unless otherwise noted, the term "halogenated
C.sub.1-4alkyl" shall mean any C.sub.1-4alkyl group as defined
above substituted with at least one halogen atom, preferably
substituted with a least one fluoro atom. Suitable examples include
but are not limited to --CF.sub.3, --CH.sub.2--CF.sub.3,
--CF.sub.2--CF.sub.2--CF.sub.2--CF.sub.3, and the like. Similarly,
the term "fluorinated C.sub.1-4alkyl" shall mean any C.sub.1-4alkyl
group as defined above substituted with at least one fluoro atom.
Suitable examples include but are not limited to --CF.sub.3,
--CH.sub.2--CF.sub.3, --CF.sub.2--CF.sub.2--CF.sub.2--CF.sub.3, and
the like.
As used herein, unless otherwise noted, the term "hydroxy
substituted C.sub.1-4alkyl" shall mean a straight or branched chain
C.sub.1-4alkyl, wherein the C.sub.1-4alkyl is substituted with one
or more, preferably one to three hydroxy groups, more preferably
one to two hydroxy groups. Most preferably, the C.sub.1-4alkyl
group is substituted with one hydroxy group. Preferably, wherein
the C.sub.1-4alkyl group has a terminal carbon atom, the hydroxy
group is bound at said terminal carbon atom.
As used herein, unless otherwise noted, the term "alkenyl" whether
used alone or as part of a substituent group, shall include
straight and branched chains containing at least one, preferably
one to three, more preferably one to two, unsaturated double bonds.
For example, alkenyl radicals include --CH.dbd.CH.sub.2,
2-propenyl, 3-butenyl, 2-butenyl, 3,7-dimethyl-octa-2,6-dienyl, and
the like. Similarly, the term "C.sub.2-8alkenyl" shall include
straight and branched alkenyl chains comprising two to eight carbon
atoms.
As used herein, unless otherwise noted, the term "alkynyl" whether
used alone or as part of a substituent group, shall include
straight and branched chains containing at least one, preferably
one to three, more preferably one to two, most preferably one,
unsaturated triple bonds. For example, alkynyl radicals include
--CCH (i.e. ethynyl), 2-propynyl, 3-butynyl, and the like.
Similarly, the term "C.sub.2-8alkynyl" shall include straight and
branched alkynyl chains comprising two to eight carbon atoms.
As used herein, unless otherwise noted, "alkoxy" shall denote an
oxygen ether radical of the above described straight or branched
chain alkyl groups. For example, methoxy, ethoxy, n-propoxy,
sec-butoxy, t-butoxy, n-hexyloxy and the like.
As used herein, unless otherwise noted, the term "halogenated
C.sub.1-4alkoxy" shall mean any C.sub.1-4alkoxy group as defined
above substituted with at least one halogen atom, preferably
substituted with a least one fluoro atom. Suitable examples include
but are not limited to --OCF.sub.3, --OCH.sub.2--CF.sub.3,
--OCF.sub.2--CF.sub.2--CF.sub.2--CF.sub.3, and the like. Similarly,
the term "fluorinated C.sub.1-4alkoxy" shall mean any
C.sub.1-4alkoxy group as defined above substituted with at least
one fluoro atom. Suitable examples include but are not limited to
--OCF.sub.3, --OCH.sub.2--CF.sub.3,
--OCF.sub.2--CF.sub.2--CF.sub.2--CF.sub.3, and the like.
As used herein, unless otherwise noted, "aryl" shall refer to fully
conjugated aromatic ring structures such as phenyl, naphthyl, and
the like.
As used herein, unless otherwise noted, the term "cycloalkyl" shall
mean any stable monocyclic, bicyclic, polycyclic, bridged or
spiro-bound, saturated ring system. Suitable examples include, but
are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, norboranyl, adamantyl,
spiropentane, 2,2,2-bicyclooctyl, and the like. Further, the term
"C.sub.5-7cycloalkyl" shall mean a cycloalkyl as herein defined
containing 5 to 7 carbon atoms. Unless otherwise noted,
"cycloalkyl" groups do not contain N, O or S heteroatoms.
As used herein, unless otherwise noted, the term "partially
unsaturated carbocyclyl" shall mean any stable monocyclic,
bicyclic, polycyclic, bridge or spiro-bound ring system containing
at least one carbon atom which is not part of an unsaturated bond
(i.e. a double or triple bond) or any bicyclic, polycyclic, bridged
or spiro-bound, partially aromatic (e.g. benzo-fused) rings system.
Suitable examples include, but are not limited to
1,2,3,4-tetrahydro-naphthyl, fluorenyl, 9,10-dihydroanthracenyl,
indanyl, and the like. Unless otherwise noted, "partially
unsaturated carbocyclyl" groups do not contain N, O or S
heteroatoms.
As used herein, unless otherwise noted, "heteroaryl" shall denote
any five or six membered monocyclic aromatic ring structure
containing at least one heteroatom selected from the group
consisting of O, N and S, optionally containing one to three
additional heteroatoms independently selected from the group
consisting of O, N and S; or a nine or ten membered bicyclic
aromatic ring structure containing at least one heteroatom selected
from the group consisting of O, N and S, optionally containing one
to four additional heteroatoms independently selected from the
group consisting of O, N and S. The heteroaryl group may be
attached at any heteroatom or carbon atom of the ring such that the
result is a stable structure.
Examples of suitable heteroaryl groups include, but are not limited
to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl,
isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl,
indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl,
benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl,
quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,
5-tetrazolyl, and the like.
As used herein, the term "heterocycloalkyl" shall denote any five
to seven membered monocyclic, saturated or partially unsaturated
ring structure containing at least one heteroatom selected from the
group consisting of O, N and S, optionally containing one to three
additional heteroatoms independently selected from the group
consisting of O, N and S; or a nine to ten membered saturated,
partially unsaturated or partially aromatic (e.g. benzo-fused)
bicyclic ring system containing at least one heteroatom selected
from the group consisting of O, N and S, optionally containing one
to four additional heteroatoms independently selected from the
group consisting of O, N and S; or a 7-16 membered saturated,
partially unsaturated or partially aromatic polycyclic or bridged
ring system containing at least one heteroatom selected from the
group consisting of O, N and S, optionally containing one or four
additional heteroatoms indepdently selected from O, N and S. The
heterocycloalkyl group may be attached at any heteroatom or carbon
atom of the ring such that the result is a stable structure.
Examples of suitable heterocycloalkyl groups include, but are not
limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,
imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,
morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,
indolinyl, chromenyl, 3,4-methylenedioxyphenyl,
2,3-dihydrobenzofuryl, tetrahydropyranyl, azepinyl,
2,3-dihydro-1,4-benzodioxanyl, 1-aza-bicyclo[2.2.2]octanyl,
3-quinuclidinyl, and the like.
As used herein, the notation "*" shall denote the presence of a
stereogenic center.
When a particular group is "substituted" (e.g., cycloalkyl, aryl,
heterocycloalkyl, heteroaryl, etc.), that group may have one or
more substituents, preferably from one to five substituents, more
preferably from one to three substituents, most preferably from one
to two substituents, independently selected from the list of
substituents.
With reference to substituents, the term "independently" means that
when more than one of such substituents is possible, such
substituents may be the same or different from each other.
Under standard nomenclature used throughout this disclosure, the
terminal portion of the designated side chain is described first,
followed by the adjacent functionality toward the point of
attachment. Thus, for example, a
"phenyl-(C.sub.1-C.sub.6alkyl)-aminocarbonyl-(C.sub.1-C.sub.6alkyl)-"
substituent refers to a group of the formula
##STR00015##
Unless otherwise noted, the position at which substituent groups on
the compounds of formula (I) are bound to the 2-amino-quinoline
core shall be denoted as follows:
##STR00016##
One skilled in the art will recognize that some substituent groups
are bivalent (i.e. bound through two points of attachment), for
example the substituent groups of A.sup.1 and L.sup.1 in the
compounds of formula (I) and formula (II) as described herein. One
skilled in the art will further recognize that the bivalency of
these groups is defined by the two bond indicators--i.e. dashes--in
the listing of said groups. For example, in the definition of
A.sup.1, the group --C.sub.1-4-alkyl- is intended to mean an alkyl
chain comprising one to four carbon atoms, wherein the chain is
bivalent. Similarly, the A.sup.1 group --CH.sub.2-cyclopropyl- is
intended that the -cyclopropyl- group is bivalent and therefore
bound into the molecule such that one carbon atom is bound to the
--CH.sub.2-- group of A.sup.1 and at another carbon atom is bound
to the rest of the molecule as defined herein.
Abbreviations used in the specification, particularly the Schemes
and Examples, are as follows:
TABLE-US-00003 Ac = Acetyl (i.e. --C(O)--CH.sub.3) AD = Alzheimer's
Disease APP = Amyloid Precursor Protein BACE = Beta Amyloid Site
Cleaving Enzyme BH.sub.3.cndot.THF = Borane Tetrahydrofuran Complex
DCM = Dichloromethane DIPEA or DIEA = Diisopropylethylamine DMAP =
4-N,N-Dimethylaminopyridine DMF = N,N-Dimethylformamide DMSO =
Dimethylsulfoxide EDC or EDCI =
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochoride
Et.sub.2O = Diethyl Ether EtOAc = Ethyl acetate EtOH = Ethanol HBTU
= O-Benzotriazol-1-yl-N, N, N', N'- tetramethyluronium
hexafluorophosphate HOBT or 1-HOBt = 1-Hydroxybenzotriazole HPLC =
High Pressure Liquid Chromatography LC/MS = Liquid
Chromatography/Mass Spectrometry LHMDS = Lithium
hexamethylisilazide MCI = Mild Cognitive Impairment MeOH = Methanol
NH.sub.4OAc = Ammonium Acetate NMR = Nuclear Magnetic Resonance
Pd(PPh.sub.3).sub.4 = Tetrakis(triphenylphosphine) palladium OM99-2
= 4-amino-4-{1-[2-carbamoyl-1-(4-{1-[3-carboxy-1-
(1-carboxy-2-phenyl-ethylcarbamoyl)-
propylcarbamoyl]-ethylcarbamoyl}-2-hydroxy-1-
isobutyl-pentylcarbamoyl)-ethylcarbamoyl]-2-
methyl-propylcarbamoyl}-butyric acid t-BuOH = tert-butanol
(HO--C(CH.sub.3).sub.3) TEA = Triethylamine TFA = Trifluoroacetic
Acid THF = Tetrahydrofuran
As used herein, unless otherwise noted, the term "isolated form"
shall mean that the compound is present in a form which is separate
from any solid mixture with another compound(s), solvent system or
biological environment. In an embodiment of the present invention,
the compound of formula (I) is present as an isolated form.
As used herein, unless otherwise noted, the term "substantially
pure compound" shall mean that the mole percent of impurities in
the isolated base is less than about 5 mole percent, preferably
less than about 2 mole percent, more preferably, less than about
0.5 mole percent, most preferably, less than about 0.1 mole
percent. In an embodiment of the present invention, the compound of
formula (I) is substantially pure.
As used herein, unless otherwise noted, the term "substantially
free of a corresponding salt form(s)" when used to described the
compound of formula (I) shall mean that mole percent of the
corresponding salt form(s) in the isolated base of formula (I) is
less than about 5 mole percent, preferably less than about 2 mole
percent, more preferably, less than about 0.5 mole percent, most
preferably less than about 0.1 mole percent. In an embodiment of
the present invention, the compound of formula (I) is substantially
free of corresponding salt forms.
The term "subject" as used herein, refers to an animal, preferably
a mammal, most preferably a human, who is or has been the object of
treatment, observation or experiment.
The term "therapeutically effective amount" as used herein, means
that amount of active compound or pharmaceutical agent that elicits
the biological or medicinal response in a tissue system, animal or
human that is being sought by a researcher, veterinarian, medical
doctor or other clinician, which includes alleviation of the
symptoms of the disease or disorder being treated.
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified
amounts, as well as any product which results, directly or
indirectly, from combinations of the specified ingredients in the
specified amounts.
Where the compounds according to this invention have at least one
chiral center, they may accordingly exist as enantiomers. Where the
compounds possess two or more chiral centers, they may additionally
exist as diastereomers. It is to be understood that all such
isomers and mixtures thereof are encompassed within the scope of
the present invention. Preferably, wherein the compound is present
as an enantiomer, the enantiomer is present at an enantiomeric
excess of greater than or equal to about 80%, more preferably, at
an enantiomeric excess of greater than or equal to about 90%, more
preferably still, at an enantiomeric excess of greater than or
equal to about 95%, more preferably still, at an enantiomeric
excess of greater than or equal to about 98%, most preferably, at
an enantiomeric excess of greater than or equal to about 99%.
Similarly, wherein the compound is present as a diastereomer, the
diastereomer is present at an diastereomeric excess of greater than
or equal to about 80%, more preferably, at an diastereomeric excess
of greater than or equal to about 90%, more preferably still, at an
diastereomeric excess of greater than or equal to about 95%, more
preferably still, at an diastereomeric excess of greater than or
equal to about 98%, most preferably, at an diastereomeric excess of
greater than or equal to about 99%.
Furthermore, some of the crystalline forms for the compounds of the
present invention may exist as polymorphs and as such are intended
to be included in the present invention. In addition, some of the
compounds of the present invention may form solvates with water
(i.e., hydrates) or common organic solvents, and such solvates are
also intended to be encompassed within the scope of this
invention.
For use in medicine, the salts of the compounds of this invention
refer to non-toxic "pharmaceutically acceptable salts." Other salts
may, however, be useful in the preparation of compounds according
to this invention or of their pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable salts of the compounds include
acid addition salts which may, for example, be formed by mixing a
solution of the compound with a solution of a pharmaceutically
acceptable acid such as hydrochloric acid, sulfuric acid, fumaric
acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric
acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore,
where the compounds of the invention carry an acidic moiety,
suitable pharmaceutically acceptable salts thereof may include
alkali metal salts, e.g., sodium or potassium salts; alkaline earth
metal salts, e.g., calcium or magnesium salts; and salts formed
with suitable organic ligands, e.g., quaternary ammonium salts.
Thus, representative pharmaceutically acceptable salts include, but
are not limited to, the following: acetate, benzenesulfonate,
benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide,
calcium edetate, camsylate, carbonate, chloride, clavulanate,
citrate, dihydrochloride, edetate, edisylate, estolate, esylate,
fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isothionate, lactate, lactobionate,
laurate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate,
N-methylglucamine ammonium salt, oleate, pamoate (embonate),
palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,
salicylate, stearate, sulfate, subacetate, succinate, tannate,
tartrate, teoclate, tosylate, triethiodide and valerate.
Representative acids which may be used in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
the following: acetic acid, 2,2-dichloroactic acid, acylated amino
acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,
benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,
(+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucoronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid, lactobionic acid,
maleic acid, (-)-L-malic acid, malonic acid, (.+-.)-DL-mandelic
acid, methanesulfonic acid, naphthalene-2-sulfonic acid,
naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,
nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid,
palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid,
salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid,
succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid,
thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.
Representative bases which may be used in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
the following: ammonia, L-arginine, benethamine, benzathine,
calcium hydroxide, choline, deanol, diethanolamine, diethylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,
N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium
hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium
hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium
hydroxide, triethanolamine, tromethamine and zinc hydroxide.
The present invention includes within its scope prodrugs of the
compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds which are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
To provide a more concise description, some of the quantitative
expressions given herein are not qualified with the term "about".
It is understood that whether the term "about" is used explicitly
or not, every quantity given herein is meant to refer to the actual
given value, and it is also meant to refer to the approximation to
such given value that would reasonably be inferred based on the
ordinary skill in the art, including approximations due to the
experimental and/or measurement conditions for such given
value.
As used herein, unless otherwise noted, the term "leaving group"
shall mean a charged or uncharged atom or group which departs
during a substitution or displacement reaction. Suitable examples
include, but are not limited to, Br, Cl, I, mesylate, tosylate, and
the like.
As used herein, unless otherwise noted, the term "nitrogen
protecting group" shall mean a group which may be attached to a
nitrogen atom to protect said nitrogen atom from participating in a
reaction and which may be readily removed following the reaction.
Suitable nitrogen protecting groups include, but are not limited to
carbamates--groups of the formula --C(O)O--R wherein R is for
example methyl, ethyl, t-butyl, benzyl, phenylethyl,
CH.sub.2.dbd.CH--CH.sub.2--, and the like; amides--groups of the
formula --C(O)--R' wherein R' is for example methyl, phenyl,
trifluoromethyl, and the like; N-sulfonyl derivatives--groups of
the formula --SO.sub.2--R'' wherein R'' is for example benzyl,
tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,
2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable
nitrogen protecting groups may be found in texts such as T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1999.
As used herein, unless otherwise noted, the term "oxygen protecting
group" shall mean a group which may be attached to an oxygen atom
to protect said oxygen atom from participating in a reaction and
which may be readily removed following the reaction. Suitable
examples include, but are not limited to methyl, benzyl,
trimethylsilyl, tert-butyldimethylsilyl, acetate, 1-ethoxyethyl,
and the like. Other suitable nitrogen protecting groups may be
found in texts such as T. W. Greene & P. G. M. Wuts, Protective
Groups in Organic Synthesis, John Wiley & Sons, 1991.
One skilled in the art will recognize that wherein a reaction step
of the present invention may be carried out in a variety of
solvents or solvent systems, said reaction step may also be carried
out in a mixture of the suitable solvents or solvent systems.
One skilled in the art will recognize that, in the specification
and claims as presented herein, wherein a reagent or reagent
class/type (e.g. base, solvent, etc.) is recited in more than one
step of a process, the individual reagents are independently
selected for each reaction step and may be the same of different
from each other. For example wherein two steps of a process recite
an organic or inorganic base as a reagent, the organic or inorganic
base selected for the first step may be the same or different than
the organic or inorganic base of the second step.
Where the processes for the preparation of the compounds according
to the invention give rise to mixture of stereoisomers, these
isomers may be separated by conventional techniques such as
preparative chromatography or recrystallization. The compounds may
be prepared in racemic form, or individual enantiomers may be
prepared either by enantiospecific synthesis or by resolution. The
compounds may, for example, be resolved into their component
enantiomers by standard techniques, such as the formation of
diastereomeric pairs by salt formation with an optically active
acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or
(+)-di-p-toluoyl-L-tartaric acid followed by fractional
crystallization and regeneration of the free base. The compounds
may also be resolved by formation of diastereomeric esters or
amides, followed by chromatographic separation and removal of the
chiral auxiliary. Alternatively, the compounds may be resolved
using a chiral HPLC column.
During any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect
sensitive or reactive groups on any of the molecules concerned.
This may be achieved by means of conventional protecting groups,
such as those described in Protective Groups in Organic Chemistry,
ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P.
G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley
& Sons, 1999. The protecting groups may be removed at a
convenient subsequent stage using methods known from the art.
Compounds of formula (I) wherein L.sup.1 is --C(O)--NR.sup.C-- may
be prepared according to the process outlined in Scheme 1.
##STR00017## ##STR00018##
Accordingly, a suitably substituted compound of formula (X), a
known compound or compound prepared by known methods is reacted
with cyanomethyl-phosphonic acid diethyl ester, a known compound,
in the presence of an organic amine such as NH.sub.4OAc,
piperidine, pyridine, and the like, in the presence of an acid such
as acetic acid, formic acid, .beta.-alanine, and the like, in an
organic solvent such as toluene, ethanol, methanol, and the like,
to yield the corresponding compound of formula (XI).
The compound of formula (XI) is reacted with a suitably substituted
compound of formula (XII), a known compound or compound prepared by
known methods, in the presence of a catalyst such as CuI, CuBr, and
the like, in an organic solvent such as THF, diethyl ether, and the
like, to yield the corresponding compound of formula (XIII).
The compound of formula (XIII) is reacted with a suitably
substituted compound of formula (XIV), a known compound or compound
prepared by known methods, in the presence of a base such as LHMDS,
lithium diisopropylamide, sodium hydride, and the like, in an
organic solvent such as THF, diethyl ether, and the like, at a
temperature in the range of from about 60.degree. C. to about
150.degree. C., preferably at a temperature in the range of from
about 75.degree. C. to about 100.degree. C., to yield a mixture of
the corresponding compound of formula (XV), as a mixture of its
corresponding (Z) and (E) isomers.
The compound of formula (XV) is reacted with a reducing agent such
as zinc, and the like, preferably zinc, in the presence of a proton
source such as ammonium chloride, calcium chloride, and the like,
in an organic solvent such as methanol, ethanol, and the like, at a
temperature in the range of from about 60.degree. C. to about
150.degree. C., preferably at a temperature in the range of from
about 75.degree. C. to about 100.degree. C., to yield the
corresponding compound of formula (XVII). Alternatively, the
compound of formula (XV) is reacted with a reducing agent such as
stannous chloride, iron, and the like, in an acidic solvent such as
aqueous HCl, acetic acid, and the like, at a temperature in the
range of from about 60.degree. C. to about 150.degree. C.,
preferably at a temperature in the range of from about 75.degree.
C. to about 100.degree. C., to yield the corresponding compound of
formula (XVII).
The compound of formula (XVII) is optionally reacted with a
suitable protecting reagent, such as acetic anhydride, acetyl
chloride, and the like, according to known methods, (i.e. in the
presence of a base such as TEA, DMAP, and the like, in an organic
solvent such as dichloromethane, chloroform, and the like) to yield
the corresponding compound of formula (XVIII), wherein Pg.sup.1 is
the corresponding suitable nitrogen protecting group.
The compound of formula (XVIII) is reacted with an oxidizing agent
such as potassium permanganate, osmium tetroxide, ruthenium
tetroxide, sodium periodate, and the like, in a mixture of an
organic solvent such as DCM, acetone, ethyl acetate, and the like,
and water (as a co-solvent), to yield the corresponding compound of
formula (XIX).
The compound of formula (XIX) is reacted with a suitably
substituted compound of formula (XX), a known compound or compound
prepared by known methods, in the presence of a coupling agent such
as HBTU, EDCl, HOBT, and the like, in the presence of a base such
as DIPEA, TEA, pyridine, and the like, in an organic solvent such
as DMF, DCM, and the like, to yield the corresponding compound of
formula (XXI).
The compound of formula (XXI) is de-protected according to known
methods, for example by reacting with hydrazine, sodium hydroxide,
and the like, in a protic solvent such as methanol or ethanol, at a
temperature in the range of from about 60.degree. C. to about
150.degree. C., preferably at a temperature in the range of from
about 75.degree. C. to about 100.degree. C., to yield the
corresponding compound of formula (Ia).
Alternatively, compounds of formula (I) wherein L.sup.1 is
--C(O)--NR.sup.C-- may alternatively be prepared according to the
process outlined in Scheme 2.
##STR00019##
Accordingly, a compound of formula (XVII) is reacted with an
oxidizing agent such as potassium permanganate, osmium tetroxide,
ruthenium tetroxide, and sodium periodate and the like, in a
mixture of an organic solvent such as DCM, acetone, ethyl acetate,
and the like, and water (as a co-solvent), to yield the
corresponding compound of formula (XXII).
The compound of formula (XXII) is reacted via a two step, one pot
reaction, first with an alkyl chloroformate, such as iso-butyl
chloroformate, and the like, in the presence of a base such as
N-methylmorpholine, DIPEA, and the like, in an organic solvent such
as dichloromethane, chloroform and the like, at a temperature less
than about room temperature, preferably at a about 0.degree. C.;
and then with a suitably substituted compound of formula (XX), a
known compound or compound prepared by known methods, yield the
corresponding compound of formula (Ia).
Compounds of formula (I) wherein L.sup.1 is --NR.sup.C-- may be
prepared according to the process outlined in Scheme 3, below.
##STR00020##
Accordingly, a suitably substituted compounds of formula (XXIII)
(as a mixture of the corresponding (Z) and (E) isomers), wherein
A.sup.0 is --(C.sub.1-3alkyl)-, a known compound or compound
prepared by known methods, is reacted with an oxidizing agent such
as potassium permanganate, osmium tetroxide, ruthenium tetroxide,
sodium periodate and the like, in the presence of
N-morpholineoxide, 2,6-lutidine, and the like; in a mixture of an
organic solvent such as THF, t-BuOH, 1,4-dioxane, and the like, and
water (as a co-solvent), to yield the corresponding compound of
formula (XXIV) (as a mixture of the corresponding (Z) and (E)
isomers).
The compound of formula (XXIV) is reacted with a suitably
substituted compound (XX), in the presence of a reducing agent,
such as sodium triacetoxyborohydride, and the like, in an organic
solvent, such as dichloromethane, dichloroethane, THF, and the
like, or sodium borohydride in a protic solvent such as methanol or
ethanol, or the like, to yield the corresponding compound of
formula (XXV) (as a mixture of the corresponding (Z) and (E)
isomers). Alternatively, the compound of formula (XXIV) is reacted
with a suitably substituted compound (XX), in the presence of
sodium cyanoborohydride, in the presence of a catalytic amount of
an acid, such as acetic acid, HCl, the like, in an organic solvent,
such as methanol, acetonitrile, and the like, to yield the
corresponding compound of formula (XXV).
The compound of formula (XXV) (as a mixture of corresponding (Z)
and (E) isomers) is reacted with a reducing agent such as zinc, and
the like, in the presence of a proton source such as ammonium
chloride, calcium chloride, and the like, in an organic solvent
such as methanol, ethanol, and the like, at a temperature in the
range of from about 60.degree. C. to about 150.degree. C.,
preferably at a temperature in the range of form about 75.degree.
C. to about 100.degree. C., to yield the corresponding compound of
formula (Ib). Alternatively, the compound of formula (XXV) is
reacted with a reducing agent such as stannous chloride, iron, and
the like, in an acidic solvent such as aqueous HCl, acetic acid,
and the like, at a temperature in the range of from about
60.degree. C. to about 150.degree. C., preferably at a temperature
in the range of form about 75.degree. C. to about 100.degree. C.,
to yield the corresponding compound of formula (Ib).
Compounds of formula (I) wherein -A.sup.1-L.sup.1 is
--(C.sub.2-4alkyl)-NRC-- may alternatively be prepared from the
corresponding compound of formula (Ic) wherein A.sup.0 is
(C.sub.1-3alkyl) as outlined in Scheme 4 below.
##STR00021##
Accordingly, a suitably substituted compound of formula (Ic),
wherein -A.sup.0- is --(C.sub.1-3alkyl)-is by reacting the compound
of formula (Ic) with a suitably selected reducing agent such as
borane-tetrahydrofuran, lithium aluminum hydride, and the like, in
an organic solvent such as diethyl ether, THF, glyme, diglyme, and
the like, at a temperature in the range of form about 25.degree. C.
to about 15.degree. C., preferably at a temperature in the range of
from about 50.degree. C. to about 100.degree. C., optionally in a
microwave, to yield the corresponding compound of formula (Ib).
Compounds of formula (I) wherein L.sup.1 is --C(O)--NR.sup.C-- may
alternatively be prepared according to the process outlined in
Scheme 5.
##STR00022##
Accordingly, a suitably substituted compound of formula (XIII), a
known compound or compound prepared by known methods, is reacted
with an oxidizing agent such as potassium permanganate, osmium
tetroxide or N-methylmorpholineoxide, ruthenium tetroxide, sodium
periodate or periodic acid, with ruthenium oxide, ruthenium
trichloride, and the like, in a mixture of an organic solvent such
as DCM, acetone, ethyl acetate, and the like, and water (as a
co-solvent), to yield the corresponding compound of formula
(XXVI).
The compound of formula (XXVI) is reacted with a suitably
substituted compound of formula (XIV), a known compound or compound
prepared by known methods, in the presence of a base such as LHMDS,
lithium diisopropylamide, sodium hydride, and the like, in an
organic solvent such as THF, diethyl ether, and the like, at a
temperature in the range of from about 60.degree. C. to about
150.degree. C., preferably at a temperature in the range of from
about 75.degree. C. to about 100.degree. C., to yield a mixture of
the corresponding compound of formula (XXVII), as a mixture of its
corresponding (Z) and (E) isomers.
The compound of formula (XXVII) is reacted with a suitably
substituted compound of formula (XX), a known compound or compound
prepared by known methods, in the presence of a coupling agent such
as HBTU, EDCl, HOBT, and the like, in the presence of a base such
as DIPEA, TEA, pyridine, and the like, in an organic solvent such
as DMF, DCM, and the like, to yield the corresponding compound of
formula (XXVIII).
The compound of formula (XXVIII) is reacted with a reducing agent
such as zinc, and the like, preferably zinc, in the presence of a
proton source such as ammonium chloride, calcium chloride, and the
like, in an organic solvent such as methanol, ethanol, and the
like, at a temperature in the range of from about 60.degree. C. to
about 150.degree. C., preferably at a temperature in the range of
from about 75.degree. C. to about 100.degree. C., to yield the
corresponding compound of formula (Ia). Alternatively, the compound
of formula (XXVIII) is reacted with a reducing agent such as
stannous chloride, iron, and the like, in an acidic solvent such as
aqueous HCl, acetic acid, and the like, at a temperature in the
range of from about 60.degree. C. to about 150.degree. C.,
preferably at a temperature in the range of from about 75.degree.
C. to about 100.degree. C., to yield the corresponding compound of
formula (Ia).
Compounds of formula (I) may alternatively be prepared according to
the process outlined in Scheme 6 below.
##STR00023##
Accordingly, a suitably substituted compound of formula (XXVI), a
known compound or compound prepared by known methods, is reacted
with a suitably substituted compound of formula (XX), a known
compound or compound prepared by known methods, in the presence of
a coupling agent such as HBTU, EDCl, HOBT, and the like, in the
presence of a base such as DIPEA, TEA, pyridine, and the like, in
an organic solvent such as DMF, DCM, and the like, to yield the
corresponding compound of formula (XXIX).
The compound of formula (XXIX) is reacted with a suitably
substituted compound of formula (XXX), wherein X is bromine,
iodine, or chlorine, a known compound or compound prepared by known
methods, in the presence of a base such as LHMDS, lithium
diisopropylamide, sodium hydride, and the like, in an organic
solvent such as THF, diethyl ether, and the like, at a temperature
in the range of from about 60.degree. C. to about 150.degree. C.,
preferably at a temperature in the range of from about 75.degree.
C. to about 100.degree. C., to yield a mixture of the corresponding
compound of formula (XXXI), as a mixture of its corresponding (Z)
and (E) isomers.
The compound of formula (XXXI) is reacted with a suitably
substituted compound of formula (XXXII), wherein the two R.sup.7
groups are the same or are hydroxy or taken together to form a
ring, such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
5,5-dimethyl-1,3,2-dioxaborinane, and the like, (i.e. the compound
of formula (XXXII) is the corresponding boronic acid or cyclic
borane ester), a known compound or compound prepared by known
methods, in the presence of a catalyst, such as
tetrakis(triphenylphosphine)palladium,
dichloro(diphenylphosphinoferrocene)palladium, and the like, in the
presence of a base such as potassium carbonate, sodium carbonate,
and the like, in a solvent such as ethanol, toluene, and the like,
in addition to water as a co-solvent, at a temperature in the range
of from about 60.degree. C. to about 150.degree. C., preferably at
a temperature in the range of from about 80.degree. C. to about
120.degree. C., to yield a mixture of the corresponding compound of
formula (XXXIII), as a mixture of its corresponding (Z) and (E)
isomers.
The compound of formula (XXXIII) is reacted with a reducing agent
such as zinc, and the like, preferably zinc, in the presence of a
proton source such as ammonium chloride, calcium chloride, and the
like, in an organic solvent such as methanol, ethanol, and the
like, at a temperature in the range of from about 60.degree. C. to
about 150.degree. C., preferably at a temperature in the range of
from about 75.degree. C. to about 100.degree. C., to yield the
corresponding compound of formula (Ia). Alternatively, the compound
of formula (XXVIII) is reacted with a reducing agent such as
stannous chloride, iron, and the like, in an acidic solvent such as
aqueous HCl, acetic acid, and the like, at a temperature in the
range of from about 60.degree. C. to about 150.degree. C.,
preferably at a temperature in the range of from about 75.degree.
C. to about 100.degree. C., to yield the corresponding compound of
formula (Ia).
One skilled in the art will recognize that compounds of formula (I)
wherein L.sup.1 is selected from the group consisting of
--N(R.sup.C)-- and --C(O)--N(R.sup.C)-- and wherein R.sup.C and
R.sup.2 are taken together with the nitrogen atom to which they are
bound to form a ring structure as defined herein, may be similarly
prepared according to the procedures described in Scheme 1, Scheme
2, Scheme 3, Scheme 5 and Scheme 6 above by selecting a suitably
substituted cyclic amine for the compound of formula (XX).
Compounds of formula (I) wherein A.sup.1 is --CH.sub.2CH.sub.2--,
L.sup.1 is --NR.sup.C-- and --R.sup.C and R.sup.4 are taken
together with the nitrogen atom to which they are bound to form
4-substituted-{1,2,3]-triazole may be prepared according to the
process as outlined in Scheme 7, below.
##STR00024## ##STR00025##
Accordingly, a suitably substituted compound of formula (XI), a
known compound or compound prepared by known methods, is reacted
with a suitably protected alkyl acetate, a compound of formula
(XXXIV) wherein Pg.sup.2 is a suitably selected protecting group
such as methyl, ethyl, t-butyl, benzyl, and the like, a known
compound or a compound prepared by known methods, in the presence
of a base, such as LHMDS, lithium diisopropylamine, sodium hydride,
and the like, in the presence of a catalyst such as CuI, CuBr, and
the like, in an organic solvent such as THF, diethyl ether, and the
like, to yield the corresponding compound of formula (XXXV).
The compound of formula (XXXV) is reacted with a suitably
substituted compound of formula (XIV), a known compound or compound
prepared by known methods, in the presence of a base, such as
LHMDS, lithium diisopropylamine, sodium hydride, and the like, in
an organic solvent such as THF, diethyl ether, and the like, at a
temperature in the range of from about 0.degree. C. to about
25.degree. C., to yield the corresponding compound of formula
(XXXVI).
The compound of formula (XXXVI) is de-protected according to known
methods, to yield the corresponding compound of formula (XXXVII).
For example, wherein Pg.sup.2 is tert-butyl, the compound of
formula (XXXVI) is reacted with an acid, in an organic solvent (for
example with TFA in dichloromethane, or HCl in an organic solvent,
such as diethyl ether, iso-propanol, ethyl acetate, and the like),
to yield the corresponding compound of formula (XXXVII).
Alternatively, wherein the compound of formula (XXXVI), Pg.sup.2 is
methyl, ethyl, and the like, the compound of formula (XXXVI) is
reacted with a base such as such as lithium hydroxide, sodium
hydroxide, and the like, in water or a protic solvent, such as
methanol, ethanol, and the like, to yield the corresponding
compound of formula (XXXVII).
The compound of formula (XXXVII) is reacted with a chloroformate,
such as ethyl chloroformate, iso-butyl chloroformate, and the like,
in the presence of an organic base, such as N-methylmorpholine,
DIPEA, triethylamine, and the like, in an organic solvent, such as
THF, tert-butylmethyl ether, and the like, at a temperature in the
range of from about -20.degree. C. to about 25.degree. C.,
preferably at a temperature in the range of from about 0.degree. C.
to about 25.degree. C. After a period of stirring, a reducing agent
such as sodium borohydride, lithium borohydride, Red-Al, and the
like, is added, optionally in a co-solvent, such as methanol,
ethanol, and the like, to yield the corresponding compound of
formula (XXXVIII).
The compound of formula (XXXVIII) is reacted with a suitably
selected sulfonylating agent, for example, a compound of the
formula Cl--SO.sub.2--R.sup.H, wherein R.sup.H is a suitably
selected alkyl or aryl group, such that Cl--SO.sub.2--R.sup.H is
for example mesyl chloride (Cl--SO.sub.2--CH.sub.3), tosyl chloride
(Cl--SO.sub.2-(4-methylphenyl)), and the like, in the presence of a
base such as TEA, DMAP, and the like, in an organic solvent such as
dichloromethane, chloroform, and the like, at a temperature in the
range of from about -20.degree. C. to about 25.degree. C.,
preferably, at a temperature in the range of from about 0.degree.
C. to about 25.degree. C., to yield the corresponding compound of
formula (XXXIX).
The compound of formula (XXXIX) is reacted with sodium azide,
optionally in the presence of an iodide source, such as sodium
iodide, potassium iodide, and the like, in an organic solvent such
as DMF, DMSO, and the like, at a temperature in the range of from
about 25.degree. C. to about 140.degree. C., preferably, at a
temperature in the range of from about 25.degree. C. to about
60.degree. C., to yield the corresponding compound of formula
(XXXX).
The compound of formula (XXXX) is reacted with a suitably
substituted compound of formula (XXXXI), wherein R.sup.J is
selected from the group consisting of C.sub.1-5alkyl,
--C.sub.1-4alkyl-O--C.sub.1-4alkyl, carboxy,
--C(O)O--C.sub.1-4alkyl and aralkyl, (preferably R.sup.J is
selected from the group consisting of C.sub.1-5alkyl, more
preferably R.sup.J is t-butyl), a known compound or compound
prepared by known methods, in the presence of a catalyst, such as
copper sulfate, copper (II) acetate, and the like, in the presence
of a base such as sodium ascorbate, ascorbic acid, DIPEA, and the
like, in an organic solvent such as DMF, THF, methanol, ethanol,
and the like, in the presence of water, to yield the corresponding
compound of formula (XXXXII).
The compound of formula (XXXXII) is reacted with a suitably
selected reducing agent such as zinc, and the like, in the presence
of a proton source such as ammonium chloride, calcium chloride, and
the like, in an organic solvent such as methanol, ethanol, and the
like, at a temperature in the range of from about 60.degree. C. to
about 150.degree. C., preferably, at a temperature in the range of
from about 75.degree. C. to about 100.degree. C., to yield the
corresponding compound of formula (Ic). Alternatively, the compound
of formula (XXXXII) is reacted with a reducing agent such as
stannous chloride, iron, and the like, in an acidic solvent such as
aqueous HCl, acetic acid, and the like, at a temperature in the
range of from about 60.degree. C. to about 150.degree. C.,
preferably at a temperature in the range of form about 75.degree.
C. to about 100.degree. C., to yield the corresponding compound of
formula (Ic).
Compounds of formula (XIV) are known compounds or compounds which
may be prepared according to known methods. For example, compounds
of formula (XIV) may be prepared according to the process outlined
in Scheme 8, below.
##STR00026##
Accordingly, a suitably substituted compound of formula (XXX),
wherein wherein X is bromine, iodine, or chlorine, a known compound
or compound prepared by known methods, is reacted with a suitably
substituted, a compound of formula (XXXII), wherein the two R.sup.7
groups are the same or are hydroxy or taken together in a ring,
such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
5,5-dimethyl-1,3,2-dioxaborinane, and the like, (i.e. the compound
of formula (XXXII) is the corresponding boronic acid or cyclic
borane ester), a known compound or compound prepared by known
methods, in the presence of a catalyst, such as
tetrakis(triphenylphosphine)palladium,
dichloro(diphenylphosphinoferrocene)palladium, and the like, in the
presence of a base such as potassium carbonate, sodium carbonate,
and the like, in a solvent such as ethanol, toluene, and the like,
in addition to water as a co-solvent, at a temperature in the range
of from about 60.degree. C. to about 150.degree. C., preferably at
a temperature in the range of from about 80.degree. C. to about
120.degree. C., to yield a mixture of the corresponding compound of
formula (XIV).
The present invention further comprises pharmaceutical compositions
containing one or more compounds of formula (I) with a
pharmaceutically acceptable carrier. Pharmaceutical compositions
containing one or more of the compounds of the invention described
herein as the active ingredient can be prepared by intimately
mixing the compound or compounds with a pharmaceutical carrier
according to conventional pharmaceutical compounding techniques.
The carrier may take a wide variety of forms depending upon the
desired route of administration (e.g., oral, parenteral). Thus for
liquid oral preparations such as suspensions, elixirs and
solutions, suitable carriers and additives include water, glycols,
oils, alcohols, flavoring agents, preservatives, stabilizers,
coloring agents and the like; for solid oral preparations, such as
powders, capsules and tablets, suitable carriers and additives
include starches, sugars, diluents, granulating agents, lubricants,
binders, disintegrating agents and the like. Solid oral
preparations may also be coated with substances such as sugars or
be enteric-coated so as to modulate major site of absorption. For
parenteral administration, the carrier will usually consist of
sterile water and other ingredients may be added to increase
solubility or preservation. Injectable suspensions or solutions may
also be prepared utilizing aqueous carriers along with appropriate
additives.
To prepare the pharmaceutical compositions of this invention, one
or more compounds of the present invention as the active ingredient
is intimately admixed with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques, which carrier
may take a wide variety of forms depending of the form of
preparation desired for administration, e.g., oral or parenteral
such as intramuscular. In preparing the compositions in oral dosage
form, any of the usual pharmaceutical media may be employed. Thus,
for liquid oral preparations, such as for example, suspensions,
elixirs and solutions, suitable carriers and additives include
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like; for solid oral preparations such as,
for example, powders, capsules, caplets, gelcaps and tablets,
suitable carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like. Because of their ease in administration, tablets and
capsules represent the most advantageous oral dosage unit form, in
which case solid pharmaceutical carriers are obviously employed. If
desired, tablets may be sugar coated or enteric coated by standard
techniques. For parenterals, the carrier will usually comprise
sterile water, through other ingredients, for example, for purposes
such as aiding solubility or for preservation, may be included.
Injectable suspensions may also be prepared, in which case
appropriate liquid carriers, suspending agents and the like may be
employed. The pharmaceutical compositions herein will contain, per
dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful
and the like, an amount of the active ingredient necessary to
deliver an effective dose as described above. The pharmaceutical
compositions herein will contain, per unit dosage unit, e.g.,
tablet, capsule, powder, injection, suppository, teaspoonful and
the like, of from about 0.1-1000 mg and may be given at a dosage of
from about 0.1-1000 mg/kg/day, preferably, at a dosage of from
about 0.5 to about 500 mg/kg/day, more preferably, at a dosage of
from about 0.5 to about 250 mg/kg/day, more preferably, at a dosage
of from about 0.5 to about 100 mg/kg/day, more preferably, at a
dosage of from about 1.0 to about 50 mg/kg/day. The dosages,
however, may be varied depending upon the requirement of the
patients, the severity of the condition being treated and the
compound being employed. The use of either daily administration or
post-periodic dosing may be employed.
Preferably these compositions are in unit dosage forms from such as
tablets, pills, capsules, powders, granules, sterile parenteral
solutions or suspensions, metered aerosol or liquid sprays, drops,
ampoules, autoinjector devices or suppositories; for oral
parenteral, intranasal, sublingual or rectal administration, or for
administration by inhalation or insufflation. Alternatively, the
composition may be presented in a form suitable for once-weekly or
once-monthly administration; for example, an insoluble salt of the
active compound, such as the decanoate salt, may be adapted to
provide a depot preparation for intramuscular injection. For
preparing solid compositions such as tablets, the principal active
ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose,
sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalcium phosphate or gums, and other pharmaceutical diluents,
e.g. water, to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention, or a
pharmaceutically acceptable salt thereof. When referring to these
preformulation compositions as homogeneous, it is meant that the
active ingredient is dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally
effective dosage forms such as tablets, pills and capsules. This
solid preformulation composition is then subdivided into unit
dosage forms of the type described above containing from 0.1 to
about 1000 mg, preferably, from about 0.1 to about 500 mg, of the
active ingredient of the present invention. The tablets or pills of
the novel composition can be coated or otherwise compounded to
provide a dosage form affording the advantage of prolonged action.
For example, the tablet or pill can comprise an inner dosage and an
outer dosage component, the latter being in the form of an envelope
over the former. The two components can be separated by an enteric
layer which serves to resist disintegration in the stomach and
permits the inner component to pass intact into the duodenum or to
be delayed in release. A variety of material can be used for such
enteric layers or coatings, such materials including a number of
polymeric acids with such materials as shellac, cetyl alcohol and
cellulose acetate.
The liquid forms in which the novel compositions of the present
invention may be incorporated for administration orally or by
injection include, aqueous solutions, suitably flavoured syrups,
aqueous or oil suspensions, and flavoured emulsions with edible
oils such as cottonseed oil, sesame oil, coconut oil or peanut oil,
as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions, include
synthetic and natural gums such as tragacanth, acacia, alginate,
dextran, sodium carboxymethylcellulose, methylcellulose,
polyvinyl-pyrrolidone or gelatin.
The method of treating disorders mediated by BACE described in the
present invention may also be carried out using a pharmaceutical
composition comprising any of the compounds as defined herein and a
pharmaceutically acceptable carrier. The pharmaceutical composition
may contain between about 0.1 mg and 1000 mg, preferably about 50
to 500 mg, of the compound, and may be constituted into any form
suitable for the mode of administration selected. Carriers include
necessary and inert pharmaceutical excipients, including, but not
limited to, binders, suspending agents, lubricants, flavorants,
sweeteners, preservatives, dyes, and coatings. Compositions
suitable for oral administration include solid forms, such as
pills, tablets, caplets, capsules (each including immediate
release, timed release and sustained release formulations),
granules, and powders, and liquid forms, such as solutions, syrups,
elixirs, emulsions, and suspensions. Forms useful for parenteral
administration include sterile solutions, emulsions and
suspensions.
Advantageously, one or more of the compounds of the present
invention may be administered in a single daily dose, or the total
daily dosage may be administered in divided doses of two, three or
four times daily. Furthermore, compounds for the present invention
can be administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those of ordinary skill in that art. To be administered in the form
of a transdermal delivery system, the dosage administration will,
of course, be continuous rather than intermittent throughout the
dosage regimen.
For instance, for oral administration in the form of a tablet or
capsule, the active drug component can be combined with an oral,
non-toxic pharmaceutically acceptable inert carrier such as
ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders; lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable
binders include, without limitation, starch, gelatin, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like.
The liquid forms in suitably flavored suspending or dispersing
agents such as the synthetic and natural gums, for example,
tragacanth, acacia, methyl-cellulose and the like. For parenteral
administration, sterile suspensions and solutions are desired.
Isotonic preparations which generally contain suitable
preservatives are employed when intravenous administration is
desired.
Compounds of this invention may be administered in any of the
foregoing compositions and according to dosage regimens established
in the art whenever treatment of disorders mediated by BACE is
required.
The daily dosage of the products may be varied over a wide range
from 0.01 to 10,000 mg per adult human per day, or any range
therein. For oral administration, the compositions are preferably
provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5,
1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and
1000 milligrams of the active ingredient for the symptomatic
adjustment of the dosage to the patient to be treated. An effective
amount of the drug is ordinarily supplied at a dosage level of from
about 0.1-1,000 mg/kg/day, or any range therein, preferably, at a
dosage of from about 0.5 to about 500 mg/kg/day, or any range
therein, more preferably, at a dosage of from about 0.5 to about
250 mg/kg/day, or any range therein, more preferably, at a dosage
of from about 0.5 to about 100 mg/kg/day, or any range therein,
more preferably, at a dosage of from about 1.0 to about 50
mg/kg/day or any range therein. The compounds may be administered
on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by
those skilled in the art, and will vary with the particular
compound used, the mode of administration, the strength of the
preparation, the mode of administration, and the advancement of the
disease condition. In addition, factors associated with the
particular patient being treated, including patient age, weight,
diet and time of administration, will result in the need to adjust
dosages.
One skilled in the art will recognize that, both in vivo and in
vitro trials using suitable, known and generally accepted cell
and/or animal models are predictive of the ability of a test
compound to treat or prevent a given disorder. One skilled in the
art will further recognize that human clinical trails including
first-in-human, dose ranging and efficacy trials, in healthy
patients and/or those suffering from a given disorder, may be
completed according to methods well known in the clinical and
medical arts.
The following Examples are set forth to aid in the understanding of
the invention, and are not intended and should not be construed to
limit in any way the invention set forth in the claims which follow
thereafter.
In the Examples which follow, some synthesis products are listed as
having been isolated as a residue. It will be understood by one of
ordinary skill in the art that the term "residue" does not limit
the physical state in which the product was isolated and may
include, for example, a solid, an oil, a foam, a gum, a syrup, and
the like.
Example 1
Compound #22
3-[3-(4-tert-Butyl-[1,2,3]triazol-1-yl)-1-(tetrahydro-pyran-4-yl)-propyl]--
7-ethoxy-6-(2-fluoro-phenyl)-quinolin-2-ylamine
##STR00027## Step A: 5-Bromo-4-fluoro-2-nitro-benzaldehyde
To a solution of 3-bromo-4-fluorobenzaldehyde (5.0 g, 24.6 mmol) in
H.sub.2SO.sub.4 (25 mL) at 0.degree. C. was added nitric acid (3
mL) in H.sub.2SO.sub.4 (30 mL), dropwise. The resulting mixture was
warmed to room temperature overnight. The resulting solution was
then poured slowly over ice and filtered to collect the yellow
precipitate. The precipitate was washed with H.sub.2O and dried,
then purified by silica gel chromatography eluted with a solvent
mixture of ethyl acetate and heptanes from 0:100 to 25:75 to yield
a light yellow solid.
Step B: 6,2'-Difluoro-4-nitro-biphenyl-3-carbaldehyde
A solution of the yellow solid prepared as in Step A (2.0 g, 8.0
mmol), 2-fluorobenzeneboronic acid (2.3 g, 16.1 mmol) and 2M
K.sub.2CO.sub.3 (12 mL) in dioxane (60 mL) was degassed with
nitrogen. Pd(PPh.sub.3).sub.4 (0.93 g, 8.0 mmol) was added, and the
resulting solution was degassed again and then heated to reflux for
1 hour. The resulting mixture was then diluted with EtOAc, washed
with saturated aqueous NaHCO.sub.3, and brine. After drying
(MgSO.sub.4), the resulting mixture was filtered and concentrated
in vacuo to yield a residue. Purification of the residue by silica
gel chromatography eluted with a solvent mixture of ethyl acetate
and heptanes from 0:100 to 5:95 yielded a light yellow solid.
Step C: 6-Ethoxy-2'-fluoro-4-nitro-biphenyl-3-carbaldehyde
A solution of NaH (456 mg, 11 mmol) in EtOH (50 mL) was stirred for
30 min. The light yellow solid prepared as in Step B (600 mg, 2.3
mmol) was added, and the resulting mixture was warmed to 30.degree.
C. After 3.5 hours at 30.degree. C., the bath was removed, and the
resulting mixture was stirred at room temperature overnight. The
resulting mixture was concentrated in vacuo and adsorbed directly
onto silica gel for purification. Purification by silica gel
chromatography eluted with a solvent mixture of dichloromethane and
heptanes from 0:100 to 50:50 yielded a yellow solid.
Step D: 1-Cyano-2-(tetrahydro-pyran-4-yl)-vinyl]-phosphonic acid
diethyl ester
Tetrahydropyran carboxyaldehyde (10 g, 87.6 mmol), diethyl
cyanoacetophosphonate (16.3 g, 92 mmol), acetic acid (3 mL, 50
mmol), and ammonium acetate (3 g, 38.9 mmol) were combined in
toluene (60 mL) and stirred overnight at room temperature, then
heated to 100.degree. C. for two hours and then filtered through
MgSO.sub.4. The solvent was removed to yield an oil which was
purified via silica column chromatography (50% EtOAc/heptane) to
yield an oil.
Step E:
4-Cyano-5-(6-ethoxy-2'-fluoro-4-nitro-biphenyl-3-yl)-3-(tetrahydr-
o-pyran-4-yl)-pent-4-enoic acid tert-butyl ester
To a solution of tert-butyl acetate (217 .mu.L, 1.6 mmol) in THF
(0.92 mL) at -78.degree. C., LHMDS (1.0 M in THF, 1.4 mL) was added
slowly. After 30 min of stirring at -78.degree. C.,
[1-cyano-2-(tetrahydro-pyran-4-yl)-vinyl]-phosphonic acid diethyl
ester (302 mg, 1.1 mmol) dissolved in THF (0.92 mL) was added,
followed by CuI (6.3 mg, 0.03 mmol). The resulting solution was
warmed to room temperature, stirred for 2 h, and then
6-ethoxy-2'-fluoro-4-nitro-biphenyl-3-carbaldehyde (266.0 mg,
0.9195 mmol), prepared as in Step C above, was added. The resulting
solution was stirred at room temperature for another 20 h. Ethyl
acetate was then added, and the resulting solution was washed with
hydrochloric acid solution (1.0 M) two times and with brine one
time, and then dried over magnesium sulfate. The resulting solution
was filtered and concentrated. The residue was purified on a silica
gel column eluted with a solvent mixture of ethyl acetate and
heptanes from 0:100 to 25:75 to yield a residue.
MH.sup.+=524.5
Step F:
4-Cyano-5-(6-ethoxy-2'-fluoro-4-nitro-biphenyl-3-yl)-3-(tetrahydr-
o-pyran-4-yl)-pent-4-enoic acid
To a solution of the residue prepared as in Step E (163 mg, 0.3119
mmol) in dichloromethane (2.0 mL) at room temperature was added TFA
(1.6 mL). The resulting solution was stirred at room temperature
for 1 h and then concentrated. Diethyl ether was added and the
resulting solution was extracted with sodium hydroxide solution
(1M) two times. The combined aqueous extracts were acidified with
conc. hydrochloric acid, and extracted with diethyl ether
(3.times.). The organic layers were combined and dried over
magnesium sulfate, filtered and concentrated to yield a
residue.
MH.sup.+ 468.47
Step G:
3-(6-Ethoxy-2'-fluoro-4-nitro-biphenyl-3-yl)-2-[3-hydroxy-1-(tetr-
ahydro-pyran-4-yl)-prolyl]-acrylonitrile
To a solution of the residue prepared as in Step F (111 mg, 0.237
mmol) in THF (1.2 mL) at 0.degree. C. was added N-methylmorpholine
(30.0 .mu.L, 16.6 mmol) followed by slow addition of ethyl
chloroformate (0.26 .mu.L, 0.27 mmol). The resulting solution was
stirred at 0.degree. C. for 1 h, and then sodium borohydride (0.45
mg, 1.2 mmol) was added. Methanol (0.2 mL) was added slowly into
the resulting solution, which was then stirred at room temperature
for 2 h. Ethyl acetate was added. The resulting solution was washed
with hydrochloric acid (1.0 M) twice and brine once and then was
dried over magnesium sulfate. The resulting solution was filtered
and concentrated to yield a yellow oil. The yellow oil was purified
on a silica gel column eluted with a solvent mixture of ethyl
acetate and heptanes from 0:100 to 35:65 to yield a yellow
solid.
MH.sup.+=454.49
Step H:
2-[3-Azido-1-(tetrahydro-pyran-4-yl)-propyl]-3-(6-ethoxy-2'-fluor-
o-4-nitro-biphenyl-3-yl)-acrylonitrile
To a solution of the yellow solid prepared as in Step G and
triethylamine (41 .mu.L, 0.295 mmol) in dichloromethane (1 mL) at
0.degree. C. was slowly added methanesulfonyl chloride (12.4 .mu.L,
0.16 mmol). The resulting solution was stirred at 0.degree. C. for
30 min. and then at room temperature for 30 min. The resulting
solution was diluted with dichloromethane, washed with hydrochloric
acid solution (1.0 M) and dried over magnesium sulfate. The
resulting solution was then filtered and concentrated. The residue
was dissolved in DMF (1.2 mL); sodium azide (43.5 mg, 0.67 mmol)
was added and the resulting solution was stirred at 50.degree. C.
for two hours. The resulting mixture was concentrated in vacuo,
loaded directly onto silica gel and purified by eluting with ethyl
acetate and heptanes in a 0:100 to 25:75 ratio to yield a foamy
solid.
MH.sup.+ 479.50
Step I:
2-[3-(4-tert-Butyl-[1,2,3]triazol-1-yl)-1-(tetrahydro-pyran-4-yl)-
-propyl]-3-(6-ethoxy-2'-fluoro-4-nitro-biphenyl-3-yl)-acrylonitrile
To a suspension of the foamy solid prepared as in Step H (0.056 g,
0.117 mmol) in EtOH (0.8 mL), a minimal amount of THF was added to
solubolize the compound. Next, 3,3-dimethyl-1-butyne (87 .mu.L,
0.70 mmol), sodium ascorbate (0.0046 g, 0.023 mmol), and copper
(II) sulfate pentahydrate (1.5 mg, 0.006 mmol) were, followed by
addition of a minimal amount of H.sub.2O to maintain solubility.
The resulting mixture stirred at room temperature in the dark.
Additional 3,3-dimethyl-1-butyne (87 .mu.L) was added twice more at
half hour intervals, and the resulting mixture stirred overnight.
Ethyl acetate was added, the resulting solution was washed with
saturated sodium bicarbonate solution, water, and brine, and then
was dried over magnesium sulfate to yield a residue. The residue
was purified by silica gel chromatography, eluting with ethyl
acetate and heptanes in a 0:100 to 35:65 ratio to yield a yellow
foamy solid.
MH.sup.+=561.65
Step J:
3-[3-(4-tert-Butyl-[1,2,3]triazol-1-yl)-1-(tetrahydro-pyran-4-yl)-
-prolyl]-7-ethoxy-6-(2-fluoro-phenyl)-quinolin-2-ylamine
Into a microwave vial was combined the yellow foamy solid prepared
as in Step I (0.0047 g, 0.084 mmol), Zn dust (180 mg), and solid
ammonium chloride (29 mg) in MeOH. The resulting mixture was
microwaved @ 95.degree. C. for 20 minutes. The resulting solution
was then filtered through Celite.RTM., washed with MeOH and then
dichloromethane and then was concentrated in vacuo to yield a
residue. The residue was purified by silica gel chromatography,
eluting with ethyl acetate and MeOH in a 100:0 to 90:10 ratio to
yield the title compound as a white solid.
Hydrochloric acid in diethyl ether was added and the resulting
solution was concentrated to yield the title compound as its
corresponding HCl salt, as a light yellow solid.
MH.sup.+=531.66
.sup.1H NMR free base (300 MHz, MeOD): .delta.1.15 (s, 9H),
1.30-1.35 (m, 7H, 1.71-1.86 (m, 2H), 2.37-2.6 (m, 1H), 2.72-2.88
(m, 1H), 3.31-3.41 (m, 2H), 3.82-3.87 (m, 1H), 3.95-3.97 (m, 1H),
4.14 (q, J=6.78 Hz, 2H), 4.24-4.36 (m, 2H), 7.04 (s, 1H), 7.10-7.25
(m, 2H), 7.34-7.41 (m, 2H), 7.53 (s, 2H), 7.89 (s, 1H)
Example 2
Compound #47
4-[2-Amino-6-(2-fluoro-phenyl)-quinolin-3-yl]-N-(3,3-dimethyl-butyl)-N-(2--
morpholin-4-yl-ethyl)-4-(tetrahydro-pyran-4-yl)-butyramide
##STR00028## Step A:
[1-Cyano-2-(tetrahydro-pyran-4-yl)-hex-5-enyl]-phosphonic acid
diethyl ester
In a flask, Mg (5.7 g) was placed in THF (50 mL) with an iodine
chip. The reaction mixture was vigorously stirred and heated
slightly, as 4-bromobutene (25 mL) was added. After consumption of
Mg metal, the resulting solution was cannulated into a flask
containing a mixture of
[1-cyano-2-(tetrahydro-pyran-4-yl)-vinyl]-phosphonic acid diethyl
ester (21.78 g, 79.7 mmol), prepared as described in Example 1 Step
D above, and CuI (0.3 g) with THF (30 mL). The resulting mixture
was stirred for three hours. Saturated aqueous NH.sub.4Cl solution
and ethyl acetate were then added. The organic layer was separated
and dried with MgSO.sub.4, filtered, and evaporated in vacuo to
yield an oil.
Step B:
5-Cyano-5-(diethoxy-phosphoryl)-4-(tetrahydro-pyran-4-yl)-pentano-
ic acid
To a solution of
[1-cyano-2-(tetrahydro-pyran-4-yl)-hex-5-enyl]-phosphonic acid
diethyl ester (6.26 g, 19.0 mmol) in dichloromethane (211 mL),
H.sub.2O (173 mL) and acetic acid (73 mL), was added
tetrabutylammonium bromide (127 mg) followed by the portionwise
addition of KMnO.sub.4. The resulting mixture was then stirred at
room temperature overnight. The resulting viscous solution was
cooled to 0.degree. C., and NaHSO.sub.3 was added slowly until the
mixture became clear. The layers were separated, and the organic
layer was dried over magnesium sulfate, filtered, and concentrated
to yield a residue. Heptanes was added, and the resulting mixture
was concentrated to yield a residue.
MH+ 347.35
Step C: 5-Bromo-2-nitro-benzaldehyde
Sulfuric acid (108 mL) and 3-bromobenzaldehyde (25 g, 0.135 mol)
were cooled to 0.degree. C. in a flask. Potassium nitrate (14.3 g,
0.14 mol) was added to the resulting mixture, portion wise over 1
h. The resulting mixture was stirred an additional 2 h at 0.degree.
C. For work up, the resulting mixture was poured into 2 L of ice
and then filtered to yield a solid. The solid was purified by
silica chromatography (330 g, 30% Et.sub.2O/heptane) to yield a
residue, which was recrystallized from EtOAc/heptane to yield a
solid.
Step D: 2'-Fluoro-4-nitro-biphenyl-3-carbaldehyde
A solution of 5-bromo-2-nitrobenzaldehyde (8.2 g, 36 mmol),
2-fluorobenzeneboronic acid (10.0 g, 71.6 mmol) and 2M
K.sub.2CO.sub.3 (54 mL) in dioxane (250 mL) was degassed with
nitrogen. Pd(PPh.sub.3).sub.4 (3.9 g, 3.6 mmol) was added, and the
resulting mixture was degassed again and heated to reflux for 90
minutes. The resulting mixture was then diluted with EtOAc and
washed with saturated aqueous NaHCO.sub.3 solution and brine. The
EtOAc extract was dried with MgSO.sub.4, filtered, and concentrated
in vacuo to yield a residue. The residue was purified by silica gel
chromatography eluted with ethyl acetate and heptanes from 0:100 to
5:95 to yield a yellow solid.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta.7.19-7.33 (m, 2H),
7.4-7.53 (m, 2H), 7.94 (dt, J=8.29, 1.88 Hz, 1H), 8.11 (s, 1H),
8.22 (d, J=8.67 Hz, 1H), 10.50 (s, 1H)
Step E:
5-Cyano-6-(2'-fluoro-4-nitro-biphenyl-3-yl)-4-(tetrahydro-pyran-4-
-yl)-hex-5-enoic acid
To a solution of the residue prepared as in Step B (6.7 g, 19.2
mmol) in THF (385 mL) at -78.degree. C. was slowly added LHMDS (1.0
M in THF, 41 mL). After 30 min of stirring at -78.degree. C., the
resulting mixture was warmed to room temperature, and the yellow
solid prepared as in Step D (4.7 g, 19.2 mmol) was added. The
resulting solution was stirred at room temperature for another 20
h. Ethyl acetate was then added, and the resulting solution was
washed with hydrochloric acid solution (1.0 M) and with brine, then
dried over magnesium sulfate. The resulting solution was filtered
and concentrated to yield a residue. The residue was purified on a
silica gel column eluted with a solvent mixture of dichloromethane
and MeOH (95:5) to yield a brown solid.
MH.sup.+=438.45
Step F: (3,3-Dimethyl-butyl)-(2-morpholin-4-yl-ethyl)-amine
Into a microwave reactor was placed 4-(2-chloroethyl)-morpholine
(1.5 g, 8.1 mmol), 3,3-dimethylbutylamine (2.2 mL, 16 mmol),
diisopropylethylamine (3.1 mL, 18 mmol), and acetonitrile (30 mL).
The resulting mixture was microwaved at 130.degree. C. for 30
minutes and then diluted with dichloromethane and 1N sodium
hydroxide. The layers were separated, and the organic extract was
washed with brine, dried over magnesium sulfate, filtered, and
concentrated to yield an orange oil. The oil was purified on a
silica gel column, eluting with 15% of 10:1 (MeOH:NH.sub.4OH) in
EtOAc to yield a yellow oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.0.87-0.94 (m, 9H),
1.35-1.46 (m, 2H), 2.42-2.51 (m, 8H), 2.58-2.66 (m, 1H), 2.72 (t,
J=6.03 Hz, 1H), 3.67-3.74 (m, 4H)
Step G:
5-Cyano-6-(2'-fluoro-4-nitro-biphenyl-3-yl)-4-(tetrahydro-pyran-4-
-yl)-hex-5-enoic acid
(3,3-dimethyl-butyl)-(2-morpholin-4-yl-ethyl)-amide
To a solution of the solid prepared as in Step E (3.2 g, 7.3 mmol)
in DMF (30 mL), were added the yellow oil prepared as in Step F
(1.7 g, 8.0 mmol), HBTU (4.1 g, 10.9 mmol), and DIEA (3.8 mL, 21.8
mmol). The resulting mixture was stirred 24 hours at room
temperature, then diluted with EtOAc. The resulting solution was
washed with saturated aqueous NaHCO.sub.3 and brine several times,
then dried over magnesium sulfate and concentrated to a foamy
solid. The foamy solid was purified on silica gel eluting with a
solvent mixture of dichloromethane and MeOH from 100:0 to 96:4 to
yield a brown solid.
MH.sup.+ 634.78.
Step H:
4-[2-Amino-6-(2-fluoro-phenyl)-quinolin-3-yl]-N-(3,3-dimethyl-but-
yl)-N-(2-morpholin-4-yl-ethyl)-4-(tetrahydro-pyran-4-yl)-butyramide
A mixture of the brown solid (2.25 g, 3.7 mmol) prepared as in Step
G above, zinc powder (25 g), ammonium chloride (7.8 g), MeOH (90
mL), and THF (17 mL) was heated at reflux. After three hours, the
resulting mixture was cooled to room temperature, filtered through
Celite.RTM., and washed with MeOH/dichloromethane. The filtrate was
concentrated to yield a solid which was purified on a silica gel
column, eluting with 10% of 10:1 (MeOH:NH.sub.4OH) in EtOAc to
yield the title compound as a yellow solid.
The HCl salt of the title compound was prepared by dissolving the
yellow solid (506 mg) in a small amount of ethanol and then
concentrating with 1M HCl/diethyl ether (3.times.) to yield a white
solid.
LCMS MH.sup.+ 604.80
.sup.1H NMR (HCl salt) (300 MHz, MeOD) .delta. 1.31 (d, J=7.54 Hz,
2H), 1.39-1.54 (m, 3H), 1.99 (s, 3H), 2.28-2.44 (m, 3H), 2.96 (s,
1H), 3.14-3.28 (m, 4H), 3.37 (d, J=3.01 Hz, 1H), 3.46 (s, 1H),
3.58-3.72 (m, 4H), 3.78-3.93 (m, 3H), 3.99-4.11 (m, 3H), 7.25-7.37
(m, 2H), 7.43-7.52 (m, 1H), 7.60 (td, J=7.72, 1.88 Hz, 1H), 7.80
(d, J=8.67 Hz, 1H), 7.99-8.05 (m, 1H), 8.16 (s, 1H), 8.54 (s,
1H)
Example 3
Compound #43
3-[4-[(3,3-Dimethyl-butyl)-(2-morpholin-4-yl-ethyl)-amino]-1-(tetrahydro-p-
yran-4-yl)-butyl]-6-(2-fluoro-phenyl)-quinolin-2-ylamine
##STR00029##
To the white solid (1.13 g, 1.9 mmol) prepared as in Example 2,
Step H, above in THF (190 mL) was added BH.sub.3. THF (1M in THF,
28 mL). The resulting mixture was degassed with nitrogen and then
heated at reflux. After 2.5 hours, the resulting mixture was cooled
to room temperature, and HCl was added slowly until a pH<5 was
obtained. The resulting mixture was again heated to reflux for 30
minutes, then cooled to room temperature, concentrated in vacuo to
yield a residue. The residue was adsorbed directly onto silica gel
in MeOH and purified eluting with 10% of 10:1 (MeOH:NH.sub.4OH) in
EtOAc to give yield a second residue. The second residue was
purified by Gilson HPLC (gradient elution of 20:80
CH.sub.3CN/H.sub.2O/0.1% TFA to 75:25 CH.sub.3CN/H.sub.2O/0.1% TFA)
to yield the title compound as its corresponding TFA salt. The
concentrated product was dissolved in a small amount of EtOH and
then concentrated with 1N HCl/diethyl ether (3.times.), then
concentrated with diethyl ether (2.times.) in EtOH to yield the
title compound as a white solid, as its corresponding HCl salt.
LCMS MH.sup.+ 590.81
.sup.1H NMR (300 MHz, MeOD): .delta.0.88 (s, 9H), 1.19 (t, J=7.16
Hz, 2H), 1.35-2.0 (m, 9H), 2.96-3.54 (m, 13H), 3.37-3.68 (m, 4H),
3.62 (q, J=7.03 Hz, 4H), 3.90-4.06 (m, 4H), 7.25-7.38 (m, 2H),
7.44-7.52 (m, 1H), 7.61 (td, J=7.82, 1.70 Hz, 1H), 7.79 (d, J=8.67
Hz, 1H), 8.02 (d, J=8.67 Hz, 1H), 8.19 (s, 1H), 8.57 (s, 1H)
Example 4
Compound #31
4-(2-Amino-6-thiophen-2-yl-quinolin-3-yl)-N-(3,3-dimethyl-butyl)-N-(1-meth-
yl-1H-imidazol-2-ylmethyl)-4-(tetrahydro-pyran-4-yl)-butyramide
##STR00030## Step A:
(3,3-Dimethyl-butyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amine
A solution of 1-methyl-2-imidazolecarboxaldehyde (4 g, 0.036 mol)
and 3,3-dimethylbutylamine (4.9 mL, 0.036 mol) in MeOH (100 mL) was
stirred at room temperature for 1 hour before NaBH.sub.4 (2.0 g,
0.053 mol) was added in portions. The resulting solution was
stirred at room temperature for another hour before quenching with
water. MeOH was removed under vacuum from the resulting mixture,
and the residue purified by column chromatography (0-15%
MeOH/EtOAc) to yield a light yellow liquid.
MH.sup.+ 196.2
Step B:
[1-Cyano-4-[(3,3-dimethyl-butyl)-(1-methyl-1H-imidazol-2-ylmethyl-
)-carbamoyl]-2-(tetrahydro-pyran-4-yl)-butyl]-phosphonic acid
diethyl ester
To an ice cooled solution of the light yellow liquid prepared as in
Step A above (1.8 g, 9 mmol),
5-cyano-5-(diethoxy-phosphoryl)-4-(tetrahydro-pyran-4-yl)-pentanoic
acid (3.0 g, 8.7 mmol, prepared as described in Example 2, Step B)
and HOBT (1.5 g, 11 mmol) in CH.sub.2Cl.sub.2 (100 mL), was added
TEA (2.4 mL) followed by the addition of 1,3-dimethylamino
propyl-3-ethylcarbodiimide (EDC, 2.2 g, 11 mmol). The resulting
mixture was allowed to warm to room temperature and then stirred
overnight. EtOAc (200 mL) was added. The resulting solution was
washed with dilute HCl solution (about 0.1N, 50 mL), saturated
aqueous NaHCO.sub.3 solution, and then brine. The organic layer was
dried with MgSO.sub.4, and the EtOAc was evaporated to yield an
oil.
MH.sup.+ 525.5
Step C:
6-(5-Bromo-2-nitro-phenyl)-5-cyano-4-(tetrahydro-pyran-4-yl)-hex--
5-enoic acid
(3,3-dimethyl-butyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amide
To an ice cooled solution of the oil prepared as in Step B above
(2.2 g, 4.2 mmol) in THF (10 mL), was added LHMDS (1.0M in THF, 5.0
mL) and the resulting solution was stirred for 10 min.
5-Bromo-2-nitro-benzaldehyde (1.0 g, 4.2 mmol, synthesized as
described in Example 2, Step C) in THF (10 mLI) was added, the
resulting solution was allowed to warm to room temperature and then
stirred overnight. The reaction was quenched with aqueous
NH.sub.4Cl solution, and the resulting solution was extracted with
EtOAc. The organic layer was dried with MgSO.sub.4. The EtOAc was
evaporated to yield an oil.
MH.sup.+ 600.2, 602.3
Step D:
6-(5-Bromo-2-nitro-phenyl)-5-cyano-4-(tetrahydro-pyran-4-yl)-hex--
5-enoic acid
(3,3-dimethyl-butyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amide
A solution of the oil prepared as in Step C (0.2 g, 0.33 mmol),
3-thiopheneboronic acid (0.045 g, 0.34 mmol), tetrakis
(triphenylphosphine) palladium (0) (0.02 g), and K.sub.2CO.sub.3
(0.092 g) in toluene/EtOH/water (5/2/1 mL) was refluxed one hour.
EtOAc (100 mL) was added, and the resulting solution was washed
with saturated aqueous NaCl solution. The organic layer was dried
with MgSO.sub.4, and the EtOAc was evaporated to yield an oil.
MH.sup.+ 605
Step E:
4-(2-Amino-6-thiophen-2-yl-quinolin-3-yl)-N-(3,3-dimethyl-butyl)--
N-(1-methyl-1H-imidazol-2-ylmethyl)-4-(tetrahydro-pyran-4-yl)-butyramide
A mixture of the oil prepared as in Step E above (0.2 g, 0.33
mmol), Zn dust (0.3 g) and NH.sub.4Cl (0.06 g) in MeOH (5 mL) was
subjected to microwave at 130.degree. C. for 5 min. The resulting
solid was filtered out, and the filtrate was concentrated under
vacuum to yield an oil. The oil was purified by Gilson HPLC to
yield the title compound as a white solid, as its corresponding TFA
salt.
MH.sup.+ 574.3
.sup.1H NMR (300 MHz, MeOD) .delta. 0.73 (s, 9H), 1.17-1.55 (m,
6H), 1.90-2.07 (m, 4H), 2.27-2.45 (m, 3H), 2.92 (br s, 1H), 3.36
(d, J=3.01 Hz, 1H), 3.46 (t, J=11.11 Hz, 1H), 3.86 (s, 3H), 3.91
(br s, 1H), 4.03 (dd, J=11.87, 3.58 Hz, 1H), 4.61-4.81 (m, 2H),
7.44 (d, J=1.88 Hz, 1H), 7.49 (d, J=1.88 Hz, 1H), 7.60 (d, J=1.88
Hz, 2H), 7.78 (d, J=8.67 Hz, 1H), 7.83 (t, J=2.26 Hz, 1H),
8.10-8.23 (m, 2H), 8.45 (s, 1H).
Example 5
Compound #51
4-[2-Amino-6-(2-ethoxy-phenyl)-quinolin-3-yl]-N-(3,3-dimethyl-butyl)-N-(1--
methyl-1H-imidazol-2-ylmethyl)-4-(tetrahydro-pyran-4-yl)-butyramide
##STR00031## Step A:
5-Cyano-6-(2'-ethoxy-4-nitro-biphenyl-3-yl)-4-(tetrahydro-pyran-4-yl)-hex-
-5-enoic acid
(3,3-dimethyl-butyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amide
A solution of the oil prepared as in Example 4, Step C above (0.17
g, 0.28 mmol), 2-ethoxybenzylboronic acid (0.063 g, 0.3 mmol),
tetrakis(triphenyl-phosphine) palladium (0) (0.02 g) and
K.sub.2CO.sub.3 (0.08 g) in toluene/EtOH/water (3/3/1 mL) was
refluxed overnight. EtOAc (100 mL) was added, then the resulting
solution was washed with saturated aqueous NaCl solution. The
organic layer was dried over MgSO.sub.4, and the EtOAc was
evaporated to yield an oil.
MH.sup.+ 642.5
Step B:
4-[2-Amino-6-(2-ethoxy-phenyl)-quinolin-3-yl]-N-(3,3-dimethyl-but-
yl)-N-(1-methyl-1H-imidazol-2-ylmethyl)-4-(tetrahydro-pyran-4-yl)-butyrami-
de
A mixture of the oil prepared as in Step A above (0.13 g, 0.2
mmol), Zn dust (0.2 g) and NH.sub.4Cl (0.06 g) in MeOH (5 mL) was
subjected to microwave at 130.degree. C. for 5 min. The resulting
solid was filtered out and the filtrate was concentrated under
vacuum to yield an oil. The oil was purified by Gilson HPLC to
yield the title compound as an off-white solid, as its
corresponding TFA salt.
MH.sup.+ 612.5
.sup.1H NMR (300 MHz, MeOD) .delta. 0.62 (s, 9H), 1.15 (d, J=3.39
Hz, 3H), 1.22 (t, J=6.97 Hz, 3H), 1.27-1.47 (m, 3H), 1.75-1.97 (m,
4H), 2.26 (s, 4H), 2.81 (br s, 1H), 3.28 (br s, 1H), 3.74 (s, 3H),
3.79 (br s, 1H), 3.87-3.95 (m, 1H), 3.99 (q, J=7.03 Hz, 2H),
4.55-4.67 (m, 2H), 6.91-7.05 (m, 2H), 7.26 (d, J=7.54 Hz, 2H), 7.33
(d, J=1.88 Hz, 1H), 7.38 (d, J=1.88 Hz, 1H), 7.62 (d, J=8.67 Hz,
1H), 7.88-7.96 (m, 2H), 8.35 (s, 1H)
Example 6
in vitro BACE Assay-1
This assay was run by CEREP (Catalog Ref. 761-B, Referred to SOP
No. 1C131; ERMOLIEFF, J., LOY, J. A., KOELSCH, G. and TANG, J.,
Proteolytic activation of recombinant pro-memapsin 2 (pro-BACE)
studied with new fluorogenic substrates, Biochemistry, (2000) Vol.
39, p. 12450).
More specifically the assay, run at 50 .mu.L in a 96 well plate,
evaluated the effect of test compound on the activity of the human
BACE-1 quantified by measuring the formation of
Mca-S-E-V-N-L-NH.sub.2 from
Mca-S-E-V-N-L-D-A-E-F-R-K(Dnp)-R--R--NH.sub.2, using a recombinant
enzyme.
The test compound, reference compound or water (control) was added
to a buffer containing 0.09 M sodium acetate (pH 4.5) and 0.25
.mu.g BACE-1. Compound interference with the fluorimetric detection
method due to autofluorescence was then checked by measurements at
the wavelengths defined to evaluate the enzyme activity.
Thereafter, the reaction was initiated by adding 7.5 .mu.M of the
substrate Mca-S-E-V-N-L-D-A-E-F-R-K(Dnp)-R--R--NH.sub.2 and the
mixture was incubated for 60 min at 37.degree. C. For control basal
measurement, the substrate was omitted from the reaction mixture.
Immediately after the incubation, the fluorescence intensity
emitted by the reaction product Mca-S-E-V-N-L-NH.sub.2 was measured
at .lamda.ex=320 nm and .lamda.em=405 nm using a microplate reader
(Ultra, Tecan). The standard inhibitory reference compound was
OM99-2, which was tested in each experiment at several
concentrations to obtain an inhibition curve from which its
IC.sub.50 value was calculated.
Representative compounds of the present invention were tested in
the assay as described above, with results as listed in Table 3,
below.
TABLE-US-00004 TABLE 3 % Inhibition and IC.sub.50 ID No IC.sub.50
(.mu.M) % Inh @ 1 .mu.M % Inh @ 10 .mu.M 1 34 2 59 3 35 4 71 5 6
>5.00 43 7 0.26 83 8 9 126 10 0.83 47 11 28 12 0.35 74.5 13 77
14 15 0.54 113 16 >0.62 88 17 1.40 73 18 77 19 14 20 0.89 92 21
0.69 87 22 0.15 65 23 0.57 97 24 1.40 93 25 0.32 72 26 27 1.8 91 28
0.88 74 29 1.50 54 30 31 0.42 79 98 33 34 0.39 68 35 0.33 116 36
0.50 76 37 82 38 0.47 69 39 0.35 93 41 0.45 65 42 0.32 65 43 78 45
0.53 94 46 0.36 70 47 0.37 58 49 99 50 22 51 0.32 99 52 3.60 55 53
2.20 55 54 8 55 2.40 90 56 73
Example 7
In Vivo Testing
Compounds of the present invention may be further tested for their
effectiveness in the treatment of disorders mediated by the BACE
enzyme, for example Alzheimer's disease, by testing the compounds
in an in vivo assay, for example, as disclosed in
Sirinathsinghji, D. J. S. (Merck Sharp and Dohme Research
Laboratories, Neuroscience Research Centre, Essex, UK.),Transgenic
mouse models of Alzheimer's disease, Biochemical Society
Transactions (1998), 26(3), pp 504-508;
Van Leuven, F. (Experimental Genetics Group, Center for Human
Genetics, Flemish Institute for Biotechnology (VIB), K. U. Leuven,
Louvain, Belg.), Single and multiple transgenic mice as models for
Alzheimer's disease, Progress in Neurobiology (Oxford) (2000),
61(3), pp 305-312;
Hsiao, K.; Chapman, P.; Nilsen, S.; Eckman, C.; Harigaya, Y.;
Younkin, S.; Yang, F.; Cole, G. (Dep. Neurology, Univ. Minnesota,
Minneapolis, Minn., USA), Correlative memory deficits, A.beta.
elevation, and amyloid plaques in transgenic mice, Science
(Washington, D.C.) (1996), 274(5284), pp 99-102 (Tg2576 mice);
Oddo, S.; Caccamo, A.; Shepherd, J. D.; Murphy, M. P.; Golde, T.
E.; Kayed, R.; Metherate, R.; Mattson, M. P.; Akbari, Y.; LaFerla,
F. M. (Department of Neurobiology and Behavior, University of
California, Irvine, Irvine, Calif., USA), Triple-transgenic model
of Alzheimer's disease with plaques and tangles: Intracellular
A.beta. and synaptic dysfunction, Neuron (2003), 39(3), pp 409-421
(APP Triple Transgenic Mice);
Ruberti, F.; Capsoni, S.; Comparini, A.; Di Daniel, E.; Franzot,
J.; Gonfloni, S.; Rossi, G.; Berardi, N.; Cattaneo, A.
(Neuroscience Program, International School for Advanced Studies
(SISSA), Trieste, Italy), Phenotypic knockout of nerve growth
factor in adult transgenic mice reveals severe deficits in basal
forebrain cholinergic neurons, cell death in the spleen, and
skeletal muscle dystrophy, Journal of Neuroscience (2000), 20(7),
pp 2589-2601 (AD11 mice);
Games, D.; Adams, D.; Alessandrini, R.; Barbour, R.; Berthelette,
P.; Blackwell, C.; Carr, T.; Clemens, J.; Donaldson, T.; et al.
(Athena Neurosciences, Inc., South San Francisco, Calif., USA),
Alzheimer-type neuropathology in transgenic mice overexpressing
V717F .beta.-amyloid precursor protein, Nature (London) (1995),
373(6514), pp 523-7 (V717F mice);
Neve, R. L.; Boyce, F. M.; McPhie, D. L.; Greenan, J.;
Oster-Granite, M. L. (Dep. Genetics, Harvard Medical School and
McLean Hospital, Belmont, Mass., USA), Transgenic mice expressing
APP-C100 in the brain, Neurobiology of Aging (1996), 17(2),
pp191-203 (APP-C100 mice);
and/or as disclosed in U.S. Pat. No. 5,811,633; U.S. Pat. No.
5,877,399; U.S. Pat. No. 5,672,805; U.S. Pat. No. 5,720,936; U.S.
Pat. No. 5,612,486; U.S. Pat. No. 5,580,003; U.S. Pat. No.
5,850,003; U.S. Pat. No. 5,387,742; U.S. Pat. No. 5,877,015; U.S.
Pat. No. 5,811,633; U.S. Pat. No. 6,037,521; U.S. Pat. No.
6,184,435; U.S. Pat. No. 6,187,922; U.S. Pat. No. 6,211,428; and
U.S. Pat. No. 6,340,783.
Example 8
Human Testing
Compounds of the present invention may be further tested for their
effectiveness in the treatment of disorders mediated by the BACE
enzyme, for example Alzheimer's disease, by testing the compounds
in human subjects, for example, as disclosed in
Lins, H.; Wichart, I.; Bancher, C.; Wallesch, C.-W.; Jellinger, K.
A.; Roesler, N. (Department of Neurology,
Otto-von-Guericke-University, Magdeburg, Germany),
Immunoreactivities of amyloid .beta. peptide(1-42) and total .tau.
protein in lumbar cerebrospinal fluid of patients with normal
pressure Hydrocephalus, Journal of Neural Transmission (2004),
111(3), pp 273-280;
Lewczuk, P.; Esselmann, H.; Otto, M.; Maler, J. M.; Henkel, A. W.;
Henkel, M. K.; Eikenberg, O.; Antz, C.; Krause, W.-R.; Reulbach,
U.; Kornhuber, J.; Wiltfang, J. (Department of Psychiatry and
Psychotherapy, Molecular Neurobiology Lab, University of
Erlangen-Nuremberg, Erlangen, Germany), Neurochemical diagnosis of
Alzheimer's dementia by CSF A.beta.42, A.beta.42/A.beta.40 ratio
and total tau, Neurobiology of Aging (2004), 25(3), pp 273-281;
Olsson, A.; Hoglund, K.; Sjogren, M.; Andreasen, N.; Minthon, L.;
Lannfelt, L.; Buerger, K.; Moller, H.-J.; Hampel, H.; Davidsson,
P.; Blennow, K. (Sahlgrenska University Hospital, Experimental
Neuroscience Section, Institute of Clinical Neuroscience, Goteborg
University, Moelndal, Sweden), Measurement of .alpha.- and
.beta.-secretase cleaved amyloid precursor protein in cerebrospinal
fluid from Alzheimer patients, Experimental Neurology (2003),
183(1), pp 74-80;
Wahlund, L.-O.; Blennow, K. (Karolinska Institute, Section of
Geriatric Medicine, Department of Clinical Neuroscience and Family
Medicine, Huddinge University Hospital, Stockholm, Sweden),
Cerebrospinal fluid biomarkers for disease stage and intensity in
cognitively impaired patients, Neuroscience Letters (2003), 339(2),
pp 99-102;
El Mouedden, M., Vandermeeren, M., Meert, T., Mercken, M. (Johnson
& Johnson Pharmaceutical Research and Development, Division of
Janssen Pharmaceutica N.V., Turnhoutseweg 30, Beerse, Belg.),
Development of a specific ELISA for the quantitative study of
amino-terminally truncated beta-amyloid peptides, Journal of
Neuroscience Methods (2005), 145(1-2), pp 97-105;
Vanderstichele, H., Van Kerschaver, E., Hesse, C., Davidsson, P.,
Buyse, M.-A., Andreasen, N., Minthon, L., Wallin, A., Blennow, K.,
Vanmechelen, E., (Innogenetics NV, Ghent, Belg.), Standardization
of measurement of .beta.-amyloid(1-42) in cerebrospinal fluid and
plasma, Amyloid (2000), 7(4), pp 245-258;
and/or Schoonenboom, N. S., Mulder, C., Van Kamp, G. J., Mehta, S.
P., Scheltens, P., Blankenstein, M. A., Mehta, P. D., Amyloid
.beta.38, 40, and 42 species in cerebrospinal fluid: More of the
same?, Annals of Neurology (2005), 58(1), pp 139-142.
Example 9
Prophetic Example
As a specific embodiment of an oral composition, 100 mg of the
compound prepared as in Example 2 or 3 is formulated with
sufficient finely divided lactose to provide a total amount of 580
to 590 mg to fill a size O hard gel capsule.
While the foregoing specification teaches the principles of the
present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *